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Perioperative management of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients at high thrombotic risk undergoing non-deferrable surgery remains poorly defined. Cangrelor represents a potential bridging treatment option. However, there is limited data in this

Takotsubo Syndrome (TS) is an acute heart failure syndrome with considerable risk of shock, resuscitation and death. LVEF is strongly reduced and left ventricular end-diastolic-pressure (LVEDP) is increased in almost all cases. Catecholamines are considered to play a causal role for the disease and

The epidemics of veno-venous Extracorporeal Membrane Oxygenation (VV ECMO) for acute lung failure in 2009 has prompted a wide application of this technology with increasing numbers of centers and procedures worldwide.

All studies on Mechanical Circulatory Support MCS for acute myocardial infarction related cardiogenic shock AMICS focused on its impact on in-hospital mortality; however, few data about its role on myocardial recovery are available. Retrospective study on 64 selected patients with AMI-CS and

Background Perioperative pathologic microvascular bleeding is associated with increased morbidity and mortality and could be reduced by hemostatic drugs. At the same time, safety concerns regarding existing hemostatic agents include excess mortality. Numerous trials investigating desmopressin have lacked power to detect a beneficial effect on transfusion of blood products. The authors performed a meta-analysis of 38 randomized, placebo-controlled trials (2,488 patients) investigating desmopressin in surgery and indicating at least perioperative blood loss or transfusion of blood products. Methods Pertinent studies were searched in BioMed Central, CENTRAL, and PubMed (updated May 1, 2008). Further hand or computerized searches involved recent (2003-2008) conference proceedings. Results In most of the included studies, 0.3 microg/kg desmopressin was used prophylactically over a 15- to 30-min period. In comparison with placebo, desmopressin was associated with reduced requirements of blood product transfusion (standardized mean difference = -0.29 [-0.52 to -0.06] units per patient; P = 0.01), which were more pronounced in the subgroup of noncardiac surgery and were without a statistically significant increase in thromboembolic adverse events (57/1,002 = 5.7% in the desmopressin group vs. 45/979 = 4.6% in the placebo group; P = 0.3). Conclusions Desmopressin slightly reduced blood loss (almost 80 ml per patient) and transfusion requirements (almost 0.3 units per patient) in surgical patients, without reduction in the proportion of patients who received transfusions. This meta-analysis suggests the importance of further large, randomized controlled studies using desmopressin in patients with or at risk of perioperative pathologic microvascular bleeding.

Left ventricular assist devices (LVADs) have emerged as vital life-saving therapeutic systems for patients with advanced and end-stage heart failure (HF). Despite their efficacy, VAD systems remain limited by post-implantation thrombotic complications. Shear-mediated platelet activation is the major driver of such complications in these devices. Nowadays few platelet function assays are routinely utilized in assessing the degree of platelet activation in VAD implanted patients. No assays exist that specifically target shear-mediated platelet activation. The platelet activity state (PAS) is a novel assay that has been well validated in vitro, measuring thrombin release as a surrogate for shear-mediated platelet activation. To date limited data exist as to the utility of this assay in the clinical setting. In the present study we evaluated eight LVAD patients' platelet activation level using the PAS assay. Simultaneous measurements of conventional prothrombotic and hemolysis markers, - i.e. fibrinogen and lactate dehydrogenase (LDH) - were also performed. Trends as to alteration from baseline were studied. We observed that the PAS assay allowed detection of an abnormal level of platelet activation in one patient in our series who suffered from an overt thrombosis. Interestingly in the same patient no signal of major abnormality in fibrinogen or LDH was detected. Further for 7/8 patients who were free of thrombosis, no significant level of platelet activation was detected via PAS assay, while elevation in fibrinogen and LDH were observed. As such, from our observational series it appears that the PAS assay is a sensitive and specific indicator of shear-mediated platelet activation. Further patients' experience will help elucidate the role of this promising assay in the management of LVAD implanted patients.

URPOSE:To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock.METHODS:This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality.RESULTS:The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group (p = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group (p = 0.020), and 30-day mortality was 68 vs 39 % (p = 0.072).CONCLUSION:Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged

Background Acute fulminant myocarditis (AFM) may represent a life-threatening event, characterized by rapidly progressive cardiac compromise that ultimately leads to refractory cardiogenic shock or cardiac arrest. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides effective cardiocirculatory support in this circumstance, but few clinical series are available about early and long-term results. Data from a multicenter study group are reported which analyzed subjects affected by AFM and treated with VA-ECMO during a 5-year period. Method From hospital databases, 57 patients with diagnoses of AFM treated with VA-ECMO in the past 5 years were found and analyzed. Mean age was 37.6 ± 11.8 years; 37 patients were women. At VA-ECMO implantation, cardiogenic shock was present in 38 patients, cardiac arrest in 12, and severe hemodynamic instability in 7. A peripheral approach was used with 47 patients, whereas 10 patients had a central implantation or other access. Results Mean VA-ECMO support was 9.9 ± 19 days (range, 2 to 24 days). Cardiac recovery with ECMO weaning was achieved in 43 patients (75.5%), major complications were observed in 40 patients (70.1%), and survival to hospital discharge occurred in 41 patients (71.9%). After hospital discharge (median follow-up, 15 months) there were 2 late deaths. The 5-year actual survival was 65.2% ± 7.9%, with recurrent self-recovering myocarditis observed in 2 patients (at 6 and 12 months from the first AFM event), and 1 heart transplantation. Conclusions Cardiopulmonary support with VA-ECMO provides an invaluable tool in the treatment of AFM, although major complications may characterize the hospital course. Long-term outcome appears favorable with rare episodes of recurrent myocarditis or cardiac-related events.

Cardiogenic shock (CS) is a state of systemic hypoperfusion, secondary to a deficit in cardiac contractile activity. Acute myocardial infarction (AMI) accounts for the majority of cases of CS, with a high mortality rate, despite the great improvements in revascularisation therapy. Nowadays, mechanical circulatory support (MCS) in CS often represents the only therapeutic approach able to restore systemic perfusion, determining a survival benefit. Recently, many efforts have been made to identify factors associated with mortality in patients receiving MCS devices. New insights into the pathophysiology of CS prompted the concept that the use of MCS should be considered early in the course of the disease, before the progression to multiorgan dysfunction. However, many questions remain unsolved and randomised trials in this field are hard to perform. Looking at the future, the timely implantation of temporary MCS, the correct selection of patient, the concomitant use of different temporary devices, the improvement in weaning strategies and the increasing use of durable devices as a destination or bridge therapy appear to be the most promising areas of development.

Background— We report the experience in a cohort of consecutive patients receiving extracorporeal membrane oxygenation during catheter ablation of unstable ventricular tachycardia (VT) at our center. Methods and Results— From 2010 to 2015, extracorporeal membrane oxygenation was initiated in 64 patients (average age: 63±15 years; left ventricular ejection fraction in 27±9%; cardiogenic shock in 23%, and electrical storm in 62% of patients) undergoing 74 unstable VT catheter ablation procedures. At least one VT was terminated in 81% of procedures with baseline inducible VT, and VT noninducibility was achieved in 69%. Acute heart failure occurred in 5 patients: 3 underwent emergency heart transplantation, 1 had left ventricular assist device (LVAD) implantation, and 1 patient eventually died because of subsequent mesenteric ischemia. All other patients were discharged alive. After a median follow-up of 21 months (13–28 months), VT recurrence was 33%; overall survival was 56 out of 64 patients (88%). Extracorporeal membrane oxygenation–supported ablation was the bridge to LVAD in 6.9% and to heart transplantation in 3.5% of patients. VT recurrence was related to ablation success (after 180 days of follow up: 19% when VT was noninducible, 42% if nonclinical VT was inducible, 75% when clinical VT was inducible, and 75% in untested patients, P P P =0.001) and left ventricular ejection fraction (hazard ratio 0.916; P =0.008) correlated with all-cause death, LVAD, and heart transplantation. Conclusions— Ablation of unstable VTs can be safely supported by extracorporeal membrane oxygenation, which allows rhythm stabilization with low procedure mortality, bridging decompensated patients to permanent LVAD or heart transplantation. Successful ablation is associated with better outcomes than unsuccessful ablation.

Background. Given that there is an association between the degree of hemodilution during cardiopulmonary bypass (CPB) and postoperative complications, patients-outcome might be improved if the nadir hematocrit concentration is kept within an optimal range. Smaller patients are more likely to have a low hematocrit during CPB: this phenomenon may be related, at least partially, to the extreme hemodilution induced by a large fixed CPB priming volume. Methods. Forty patients with a body surface area (BSA) < 1.7 m2 undergoing open heart operations were randomized to either standard CPB with full prime volume (control group) or reduced prime extracorporeal circuit and vacuum-assisted venous drainage (VAVD) (study group). Results. There were no significant differences between the groups with respect to baseline characteristics, body surface area, hematologic profile and operative data. Clinical outcomes were similar. Nadir hematocrit and hemoglobin on bypass were significantly lower in the control group (22 ± 2.3 vs 24 ± 2.5%, p < 0.02 and 7.4 ± 0.7 vs 8 ± 0.9g/dl, p < 0.04, respectively). Postoperative chest tube drainage was significantly higher in the control group (272 ± 253vs 139 ± 84ml, p < 0.04). There was no difference in blood transfusion in the two groups (0.5 ± 1.14 v 1.0 ± 1.77 units of packed red blood cells (PRBC), p = 0.29). Conclusions. Lowering CPB priming volume by means of using a small oxygenator and vacuum-assisted venous drainage (VAVD) resulted in a significant decrease of intraoperative hemodilution. This technique should be strongly considered for patients with a small BSA (2) undergoing open heart surgery. Perfusion (2007) 22, 317—322.

Aims: To determine if percutaneous tracheostomy is safe in critically ill patients treated with anticoagulant therapies. Settings and Design: Single-center retrospective study including all the patients who underwent percutaneous dilatational tracheostomy (PDT) placement over a 1-year period in a 14-bed, cardiothoracic and vascular Intensive Care Unit (ICU). Materials and Methods: Patients demographics and characteristics, anticoagulant and antiplatelet therapies, coagulation profile, performed technique and use of bronchoscopic guidance were retrieved. Results: Thirty-six patients (2.7% of the overall ICU population) underwent PDT over the study period. Twenty-six (72%) patients were on anticoagulation therapy, 1 patient was on antiplatelet therapy and 2 further patients received prophylactic doses of low molecular weight heparin. Only 4 patients had normal coagulation profile and were not receiving anticoagulant or antiplatelet therapies. Overall, bleeding of any severity complicated 19% of PDT. No procedure-related deaths occurred. Conclusions: PDT was proved to be safe even in critically ill-patients treated with anticoagulant therapies. Larger prospective studies are needed to confirm our findings.

Venovenous extracorporeal membrane oxygenation (VV ECMO) in acute respiratory distress syndrome (ARDS) is currently a widely used therapeutic strategy. However, patients are often still hypoxemic despite complete ECMO support. The major determinants of peripheral oxygen saturation (SpO2) during VV ECMO are pump flow, degree of recirculation, patient's systemic venous return and its oxygen saturation, hemoglobin concentration and residual lung function. Current guidelines state that the support can be considered adequate when the patient's SpO2 is equal or greater than 80%, but a possible objection could be that such a value of O2-tension may be too low and may worsen the patient's prognosis. Moving from the pathophysiology of hypoxemia during VV ECMO, this review focuses on recirculation of blood and on the possible strategies to minimize it, on the pharmacologic modulation of intrapulmonary shunt and on the questions related to management of ECMO flow and the risks and benefits of permissive hypoxemic states. Transfusional strategy during VV ECMO, administration of neuromuscular blocking agents and sedatives, therapeutic hypothermia, and prone positioning is also reviewed. The potential advantages of β-blockers are discussed. Finally, transition from VV ECMO to venoarterial ECMO (VA ECMO) or a hybrid configuration is also examined.

Aim: Spontaneous alterations in temperature homeostasis after cardiac arrest (CA) are associated with worse outcome. However, it remains unclear the prognostic role of temperature variability (TV) during cooling procedures. We hypothesized that low TV during targeted temperature management (TTM) would be associated with a favourable neurological outcome after CA. Methods: We reviewed data from all comatose patients after in-hospital or out-of-hospital CA admitted to our Department of Intensive Care between December 2006 and January 2014 who underwent TTM (32-34. °C) and survived at least 24. h. We collected demographic data, CA characteristics, intensive care unit (ICU) survival and neurological outcome at three months (favourable neurological outcome was defined as cerebral performance category 1-2). TV was expressed using the standard deviation (SD) of all temperature measurements during hypothermia; high TV was defined as an SD >1. °C. Results: Of the 301 patients admitted over the study period, 72 patients were excluded and a total of 229 patients were studied; 88 had a favourable neurological outcome. The median temperature on ICU admission was 35.8 [34.9-36.9]. °C and the median time to hypothermia (body temperature

Objective: The aim of this study was to evaluate the performance of a new temperature management system specifically designed for cardiac surgery (Allon Thermo-Wrapping Thermoregulation System; MTRE Advanced Technologies Ltd, Or Akiva, Israel) using a circulating-water garment and to compare it with a conventional forced-air cover system in order to determine whether it could reduce the incidence of perioperative hypothermia during off-pump coronary artery bypass graft (OPCAB) surgery. Design: Prospective, randomized. Setting: University, tertiary care hospital. Participants: Thirty-one patients undergoing primary OPCAB surgery. Interventions: Patients undergoing OPCAB surgery were randomized into the new thermoregulation system, Allon (study group, n = 15), and the standard forced-air system, Bair Hugger (Sterile Cardiac Access blanket Model 645; Augustine Sa, Berne, Switzerland) (control group, n = 16). Measurements and Main Results: Rectal temperature was recorded each 30 minutes during surgery and at intensive care unit arrival. Patients in the study group had higher temperatures than the control group at all time points, and the difference reached statistical significance after 2 hours of surgery. Moreover, fewer patients in the study group suffered perioperative hypothermia (defined as rectal temperature

The Levitronix CentriMag is approved in Europe for 30 days as uni- or biventricular support in acute heart failure as a bridge to recovery, bridge to heart transplantation or to a long-term left ventricular assist device (LVAD). We report the case of a patient who was supported with the same Levitronix CentriMag pump for 119 days without changing any components of the circuit or the pump head because of an anatomical condition which precluded the feasibility of pump exchange and who did not experience any mechanical failure of the impeller but eventually died due to the rupture of the cannulae. This is the first report of failure of paracorporeal short-term LVAD due to disruption of one cannula with a properly functioning pump. doi: 10.1111/jocs.12149 (J Card Surg 2013;28:472–474)

Objectives: To study the long-term survival and quality of life of patients with a complicated post-operative course after cardiac surgery requiring prolonged (greater than or equal to 7 days) mechanical ventilation (MV), since they represent a heavy burden on hospital resources and their outcome has never been adequately evaluated. Methods: Out of 4827 consecutive cardiac surgical patients, 148 (3%) required prolonged postoperative MV: their hospital course was analysed and factors affecting prolonged MV and mortality were identified using multivariate analysis. Long-term survival was assessed using Cox proportional hazard method. Long-term (36 +/- 12 months) follow-up information was collected and quality of life was assessed by an ad hoc questionnaire. Results: Overall mortality in the study group was 45.3 versus 2% in the control population (P < 0.0001). Predictors of death in the prolonged MV group were age (odds ratio, OR 1.049) and diabetes (OR 3.459). Long-term survival was significantly worse in those patients who were extubated after 21 days: 88.9 versus 70.9% at 1 year (P = 0.03) and 80.9 versus 64.5% at 5 years (P = 0.05). Mild or no limitation in daily living was referred by 69% of the survivors. Conclusions: The hospital mortality of patients requiring prolonged MV is high. The long-term survival of patients who are weaned from MV after 21 days is significantly lower. The great majority of the survivors can enjoy a good quality of life. (C) 2003 Elsevier B.V. All rights reserved.

Objective. Multi-drug resistant bacterial infections, in particular when Methicillin-Resistant Staphylococcus Aureus (MRSA) is involved, have become a relevant problem in both general and specialized intensive care units. The aim of this study was to identify the epidemiology of MRSA infections in a Cardiac Surgical Intensive Care Unit, to assess their impact on mortality and to identify predictors of MRSA infection and mortality in this population. Design and settings. A 7-year observational study in a cardiac surgery teaching center. Participants. Eight thousand, one hundred and sixty-two microbiological samples were obtained from 7,313 patients who underwent cardiac surgery in the study period. Interventions. None. Variables of interest and main results. Twenty-eight patients (0.38%) had MRSA infection. The most frequent site of MRSA isolation was from bronchoalveolar samples. Hospital mortality was 50% in patients with MRSA infection and 2% in patients without MRSA infection (p

Introduction The intra-aortic balloon pump is routinely used in cardiac surgery; however, its impact on outcome is still a matter of debate and several randomized trials have been published recently. We perform an updated meta-analysis of randomized controlled trials that investigated the use of preoperative intra-aortic balloon pump in adult patients undergoing coronary artery bypass grafting. Methods Potentially eligible trials were identified by searching the Medline, Embase, Scopus, ISI Web of Knowledge and The Cochrane Library. Searches were not restricted by language or publication status and were updated in August 2014. Randomized controlled trials on preoperative intra-aortic balloon pump in patients undergoing coronary artery bypass grafting either with or without cardiopulmonary bypass were identified. The primary end point was mortality at the longest follow-up available and the secondary end point was 30-day mortality. Results The eight included randomized clinical trials enrolled 625 patients (312 to the intra-aortic balloon pump group and 313 to control). The use of intra-aortic balloon pump was associated with a significant reduction in the risk of mortality (11 of 312 (3.5%) versus 33 of 313 (11%), risk ratio = 0.38 (0.20 to 0.73), P for effect = 0.004, P for heterogeneity = 0.7, I-square = 0%, with eight studies included). The benefit on mortality reduction was confirmed restricting the analysis to trials with low risk of bias, to those reporting 30-day follow-up and to patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Conclusions Preoperative intra-aortic balloon pump reduces perioperative and 30-day mortality in high-risk patients undergoing elective coronary artery bypass grafting.

Purpose: To evaluate the efficacy of aspirin (ASA) in inhibiting ex vivo thrombin generation in patients with durable Left Ventricular Assist Device (LVAD) and to compare the thrombin generation profile of patients administered low (100mg/day) vs high (300mg/day) ASA dose. Methods: The Thrombin Generation Test was performed on a cohort patients implanted with LVAD who did not suffer any thrombotic event (n= 14). Thrombin generation was triggered by 0.5 pmol/L Tissue Factor in normal platelet poor plasma with the addition of the patients’ purified platelets, to account for the role played by platelets in mediating thrombin generation and to exclude any influence of anticoagulation therapy (Warfarin) on the test. Patients were on different ASA dose, according to the pump model: a) HeartMate II (Thoratec Corp., USA): 100mg/day (n= 3, 21%); b) HeartMate III (St. Jude Medical Inc., USA): 100mg/day (n= 4, 29%); c) Heartware HVAD (Heartware Corp., USA): 300mg/day (n= 7, 50%). In addition, one patient with HVAD who was not on ASA because of allergy was also profiled. Results were compared with those obtained from ASA-free volunteers (controls, n= 14). Results: Following a median time of LVAD support of 210 (IQR: 138-477) days, platelet-mediated thrombin generation was comparable in ASA-treated LVAD recipients and in controls (Fig. 1A,B). Notably, the patient not on ASA (491 days of support) showed higher thrombin generation as compared to the rest of the population (Fig. 1A,B). Comparison of low vs high ASA dose revealed no differences in terms of platelet-mediated thrombin generation (Fig. 1C). Conclusion: We report that ASA inhibits ex vivo platelet-mediated thrombin generation in LVAD recipients and may eventually mitigate the risk of thrombotic complications. The thrombin generation profile of ASA-treated LVAD patients was similar to controls. Moreover, we suggest that high dose ASA does not add any significant effect in blunting platelet activation and the associated thrombin generation pattern.

Heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin which significantly confers risks of thrombosis and devastating outcomes. Once diagnosed, it requires immediate cessation of heparin and therapy with an alternative anticoagulant. No data are available in the literature on the pathophysiology and clinical implications of performing prolonged extracorporeal membrane oxygenation with a heparin-coated system in a patient with acute HIT treated with bivalirudin.

Dear Editor, The recent availability of the Avalon Elite bicaval dual lumen catheter offers a potentially less invasive approach for the extracorporeal membrane oxygenation (ECMO) treatment of severe respiratory insufficiency as compared to the femorojugular approach [1]. Nevertheless, Avalon cannula placement is more demanding and no data have been published about its effectiveness in improving oxygenation and safety concerning hemolysis, which is also an important issue, being reported in 27 % of ECMO patients [2]. In the last 2 years, we systematically adopted the bicaval dual lumen jugular approach for venovenous (VV)-ECMO treatment. Data about oxygenation and hemolysis have been collected and compared with an historical group of patients treated with the femorojugular approach (Table 1). Patients were supported with ECMO in case of severe hypoxia refractory to conventional treatment. During cannulation and 6 h after, patients were sedated. After cannulation, a respiratory rate of 10 breaths per minute, a 40 % FiO2, and a maximum tidal volume of 6 ml/kg were established. Early awakening with spontaneous ventilation and mobilization was attempted whenever possible. All recent patients were cannulated with an Avalon Elite bicaval dual lumen catheter 27 or 31 Fr under transesophageal echocardiography (TEE) imaging. No complications were observed during the procedure and all patients underwent a correct cannula placement. Moreover, most of the patients were extubated and mobilized before ECMO removal, without any issue on the cannula. Similarly, the previously used femorojugular approach with an HLS cannulae set (15–19 and 21–25 Fr) showed a correct placement under TEE imaging and no complications related to the procedure. Data in Table 1 about gas exchange refer to the first 6 h of VVECMO treatment. We considered blood flow as the major determinant of oxygenation [3]. Hemolysis was observed during the VV-ECMO support, and peak values of free hemoglobin and lactic dehydrogenase are reported. At similar pump flow (mean 3.3 vs 3.6 l/min, P = 0.106), no significant difference was observed in oxygenation parameters and hemolysis in the two groups. In our view, we cannot identify any drawbacks to the use of the Avalon Elite bicaval dual lumen catheter for VV-ECMO because oxygenation improvement and hemolysis parameters were similar to those observed with the femorojugular approach. In the light of these data, we advise that TEE-guided Avalon Elite bicaval dual lumen catheter implantation is safe and, as it allows for safe mobilization (either for

Objectives Because of its reduced invasiveness, MitraClip (Abbott Vascular, Menlo Park, CA) therapy usually is reserved for patients with extreme left ventricular dysfunction or severe comorbidity contraindicating surgery. The appropriate post-procedural care in this high-risk population is yet to be defined. In this study, the postoperative course of such patients is reported, focusing on early complications and need for intensive care unit (ICU) management. Design, Setting, and Participants A retrospective analysis of patients with severe mitral regurgitation undergoing transcatheter mitral valve repair with the MitraClip system in the authors institution was performed. Interventions One hundred thirty patients underwent MitraClip implantation between 2008 and 2012. At the end of the procedure, all patients were admitted to the ICU. Measurements and Main Results Median ICU stay was 0.98 (0.82-1.87) days. Median mechanical ventilation time was 9.5 (6.8-14.1) hours. One hundred one patients (78%) required inotropic support and 13 patients (10%) suffered cardiogenic shock and required intra-aortic balloon pump support. No patient died during the procedure, but 3 patients died in the ICU. Three postoperative course profiles were identified: Fast-track, overnight stay, and critical illness. Twenty-four patients (18.5%) had an uneventful postoperative course, 89 patients (68.5%) suffered minor complications, and 17 patients (13.1%) required intensive care management and organ support. Preoperative serum creatinine (odds ratio [OR] 1.8; p = 0.014), cardiogenic shock (OR 34,8; p = 0.002), ventricular tachycardia (OR 2.8; p = 0.03), and intra procedural inotropes (OR 4; p = 0.001) were correlated with a complicated postoperative course. Conclusions A large number of patients undergoing MitraClip could be managed with a fast-track ICU course; however, it still is difficult to predict the postoperative course based on preoperative characteristics.

Objective: To assess the very long-term clinical and echocardiographic results of the edge-to-edge repair for mitral regurgitation (MR) due to isolated prolapse or flail of the anterior leaflet. Methods: From 1991 to 2004, 139 patients (age, 54 +/- 14.4 years; left ventricular ejection fraction 56% +/- 7.8%, New York Heart Association class I-II in 68.9%, atrial fibrillation in 20.1%) with severe degenerativeMRdue to isolated segmental prolapse or flail of the anterior leaflet were treated with the EE technique combined with annuloplasty. MR had resulted from prolapse or flail of the central scallop of the anterior leaflet (A2) in 105 patients (75.5%) and scallops A1 or A3 in 34 (24.4%). Results: No hospital deaths occurred. At hospital discharge, MR was absent or mild in 130 patients (93.5%) and moderate (2+/4+) in 9 (6.4%). The clinical and echocardiographic follow-up data were 97.1% complete (mean length, 11.5 +/- 3.73 years; median, 11; longest duration, 21.5). At 17 years, the actuarial survival was 72.4% +/- 7.89%, freedom from cardiac death was 90.8% +/- 4.77%, and freedom from reoperation was 89.6% +/- 2.74%. At the last echocardiographic examination, recurrence of MR grade >= 3 vertical bar was documented in 17 patients (17 of 135, 12.5%). Freedom from MR grade >= 3+ at 17 years was 80.2% +/- 5.86%. At multivariate analysis, the predictors of MR recurrence grade >= 3+ were residual MR greater than mild at hospital discharge (hazard ratio, 7.4; 95% confidence interval, 2.5-21.2; P = .0001) and the use of posterior pericardial rather than prosthetic ring annuloplasty, which was very close to statistical significance (hazard ratio, 2.8; 95% confidence interval, 0.9-8.7; P = .06). Conclusions: In patients with MR due to segmental anterior leaflet prolapse, the very long-term results of the edge-to-edge repair combined with annuloplasty were excellent.

Background— To assess the long-term results of the edge-to-edge mitral repair performed without annuloplasty in degenerative mitral regurgitation (MR). Methods and Results— From 1993 to 2002, 61 patients with degenerative MR were treated with an isolated edge-to-edge suture without any annuloplasty. Annuloplasty was omitted in 36 patients because of heavy annular calcification and in 25 for limited annular dilatation. A double-orifice repair was performed in 53 patients and a commissural edge-to-edge in 8. Hospital mortality was 1.6%. Follow-up was 100% complete (mean length, 9.2±4.21 years; median, 9.7; longest, 18.1). Survival at 12 years was 51.3±7.75%. At the last echocardiographic examination, MR ≥3+ was demonstrated in 33 patients (55%). At 12 years, freedom from reoperation was 57.8±7.21% and freedom from recurrence of MR ≥3+ was 43±7.6%. Residual MR >1+ at hospital discharge was identified as a risk factor for recurrence of MR ≥3+ (hazard ratio, 3.8; 95% confidence interval, 1.7–8.2; P =0.001). In patients with residual MR ≤1+ immediately after surgery, freedom from MR ≥3+ at 5 and 10 years was 80±6% and 64±7.58%, respectively. Conclusions— In degenerative MR, the overall long-term results of the surgical edge-to-edge technique without annuloplasty are not satisfactory. Early optimal competence (residual MR ≤1+) was associated with higher freedom from recurrent severe regurgitation.

Importance No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. Objective To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. Interventions Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 μg/kg/min (range, 0.025-0.3 µg/kg/min). Main Outcomes and Measures The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. Results The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy ( P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group ( P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group ( P = .001). Conclusions and Relevance Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. Trial Registration clinicaltrials.gov Identifier:NCT00621790

Bivalirudin is a direct thrombin inhibitor that is increasingly used in patients undergoing mechanical circulatory support as it presents many advantages compared with unfractionated heparin. The aim of this study was to describe our experience with bivalirudin as primary anticoagulant in patients undergoing ventricular assist device (VAD) implantation. An observational study was performed on 12 consecutive patients undergoing VAD implantation at our institution. Patients received a continuous infusion of bivalirudin, with a starting dose of 0.025 mg/kg/h; the target activated partial thromboplastin time (aPTT) was between 45 and 60 s. Patients never received heparin during hospitalization nor had a prior diagnosis of heparin-induced thrombocytopenia (HIT). All patients received a continuous flow pump except one. Preoperative platelets count was 134 000 ± 64 000 platelets/mm(3) . Mean bivalirudin dose was 0.040 ± 0.026 mg/kg/h over the course of therapy (5-12 days). Lowest platelets count during treatment was 73 000 ± 23 000 platelets/mm(3) . No thromboembolic complications occurred. Two episodes of minor bleeding from chest tubes that subsided after reduction or temporary suspension of bivalirudin infusion were observed. Intensive care unit stay was 8 (7-17) days, and hospital stay was 25 (21-33) days. Bivalirudin is a valuable option for anticoagulation in patients with a VAD and can be easily monitored with aPTT. The use of a bivalirudin-based anticoagulation strategy in the early postoperative period may overcome many limitations of heparin and, above all, the risk of HIT, which is higher in patients undergoing VAD implantation. Bivalirudin should no longer be regarded as a second-line therapy for anticoagulation in patients with VAD. [Correction added on 6 December 2013, after first online publication: The dose of bivalirudin in the Abstract to 0.025 mg/kg/h].

The Levitronix CentriMag is approved in Europe for 30 days as uni- or biventricular support in acute heart failure as a bridge to recovery, bridge to heart transplantation or to a long-term left ventricular assist device (LVAD). We report the case of a patient who was supported with the same Levitronix CentriMag pump for 119 days without changing any components of the circuit or the pump head because of an anatomical condition which precluded the feasibility of pump exchange and who did not experience any mechanical failure of the impeller but eventually died due to the rupture of the cannulae. This is the first report of failure of paracorporeal short-term LVAD due to disruption of one cannula with a properly functioning pump.

A 72-year-old man presented to the emergency department in cardiogenic shock; 4-days before he was diagnosed with right femoro-popliteal deep vein thrombosis after trauma. During routine monitoring and diagnostic workup, cardiac arrest with pulseless electric activity rapidly ensued and cardiopulmonary resuscitation was initiated. A transthoracic echocardiogram showed severe right ventricular dilatation and acute pulmonary embolism was suspected. No Return of Spontaneous Circulation was obtained after 10 minutes of cardiopulmonary resuscitation. The patient was transferred to the cardiac catheterization laboratory under resuscitation with autopulse (ZOLL, Chelmsford, MA) and femoro-femoral veno-arterial extracorporeal membrane oxygenation (ECMO; PLS Maquet GmbH, Rastett, Germany) was percutaneously initiated with a 23 French (Fr) venous cannula and 17 Fr arterial cannula with restoration of systemic blood flow and oxygen delivery (5 L/min, 4000 rpm). Baseline pulmonary angiography demonstrated a large amount of thrombus in both the right (Movie I in the online-only Data Supplement) and the left pulmonary arteries …

To evaluate the efficacy of methylene blue in raising mean arterial pressure in hypotensive patients.A meta-analysis of randomised controlled trials.We searched BioMedCentral, PubMed, Embase and the Cochrane Central Register of clinical trials.Inclusion criteria were random allocation to treatment and comparison of methylene blue versus any comparator. Exclusion criteria were duplicate publications, non-adult studies and no data on main outcomes. The primary end point was mean arterial blood pressure value 1 hour after the study drug administration; the secondary end points were mortality at the longest follow-up available, and cardiac index.Data from 174 patients in five randomised controlled studies were analysed. Mean arterial pressure rose in patients receiving methylene blue (weighted mean difference = 6.93 mmHg; 95% CI, 1.67 to 12.18; P for effect = 0.01; P for heterogeneity = 0.17; I2 = 41%). Only two studies reported the values of cardiac index with a non-statistically significant improvement in the methylene blue group (mean difference = 0.76 L/min/m2; 95% CI, ? 0.32 to 1.84; P for effect = 0.2). The overall mortality rate was 16% (14/88) among methylene blue treated patients and 23% (20/86) in the control group (odds ratio = 0.65; 95% CI, 0.21 to 2.08; P for effect = 0.5).Methylene blue increases arterial blood pressure and systemic vascular resistances in vasoplegic patients without a detrimental effect on survival.

Objective To investigate the ability of early urinary neutrophil gelatinase-associated lipocalin to predict postoperative complications in adult patients with ventricular dysfunction undergoing cardiac surgery. Design Prospective observational study. Setting Single-center study, university hospital. Participants Fifty-six adult high-risk cardiac surgical patients with preoperative cardiac failure. Interventions None. Measurements and Main Results Demographic and clinical characteristics were obtained, and neutrophil gelatinase-associated lipocalin was measured at baseline and at several time points after surgery. Patient characteristics and neutrophil gelatinase-associated lipocalin levels were related to renal and patient outcome. On multivariate analyses, preoperative urinary neutrophil gelatinase-associated lipocalin was an independent predictor of length of intensive care stay (p = 0.004) and in-hospital stay (p = 0.04), but not of acute kidney injury or renal replacement therapy and was not associated with baseline renal function. Conclusions In a cohort of high-risk cardiac surgery patients, preoperative urinary neutrophil gelatinase-associated lipocalin value provided prognostic information that was independent of the onset of acute kidney injury or of preoperative renal function.

OBJECTIVES: The ‘edge-to-edge’ technique (EE) can be used as a bailout procedure in case of a suboptimal result of conventional mitral valve (MV) repair. The aim of this study was to assess the long-term outcomes of this technique used as a rescue procedure. METHODS: From 1998 to 2011, of 3861 patients submitted to conventional MV repair for pure mitral regurgitation (MR), 43 (1.1%) underwent a rescue edge-to-edge repair for significant residual MR at the intraoperative hydrodynamic test or at the intraoperative transoesophageal echocardiography. Residual MR was due to residual prolapse in 30 (69.7%) patients, systolic anterior motion in 12 (27.9%) and post-endocarditis leaflet erosion in 1 (2.3%). According to the location of the regurgitant jet, the edge-to-edge suture was performed centrally (60.5%) or in correspondence with the anterior or posterior commissure (39.5%). The original repair was left in place. RESULTS: There were no hospital deaths. Additional cross-clamp time was 15.2 ± 5.6 min. At hospital discharge, all patients showed no or mild MR and no mitral stenosis. Clinical and echocardiographic follow-up was 97.6% complete (median length 5.7 years, up to 14.6 years). At 10 years, actuarial survival was 89 ± 7.4% and freedom from cardiac death 100%. Freedom from reoperation and freedom from MR ≥3+ at 10 years were both 96.9 ± 2.9%. At the last echocardiogram, MR was absent or mild in 37 patients (88%), moderate in 4 (9.5%) and severe in 1 (2.4%). No predictors for recurrence of MR ≥2+ were identified. The mean MV area and gradient were 2.8 ± 0.6 cm 2 and 2.7 ± 0.9 mmHg. NYHA I–II was documented in all cases. CONCLUSIONS :A ‘rescue’ EE can be a rapid and effective option in case of suboptimal result of ‘conventional’ MV repair. Long-term durability of the repair is not compromised.

"OBJECTIVE:. TAVI is the alternative option in pts with AS deemed ineligible for surgery. Although mortality and morbidity are measures to assess the effectiveness of treatments, quality of life (QOL) should be an additional target. We assessed clinical outcome and QOL in octogenarians following TAVI.. DESIGN:. All octogenarians with a risk profile considered by the Heart Team to be unacceptable for surgery entered in this registry. QOL was assessed by questionnaires concerning physical and psychic performance.. PATIENTS:. A hundred forty-five octogenarians (age: 84.7 ± 3.4 years; male: 48.3%) underwent TAVI for AS (97.2%) or isolated AR (2.8%). NYHA class: 2.8 ± 0.6; Logistic EuroScore: 26.1 ± 16.7; STS score: 9.2 ± 7.7.Echocardiographic assessments included AVA (0.77 ± 0.21 cm2), mean\/peak gradients (54.5 ± 12.2\/88 ± 19.5 mm Hg), LVEF (21%=EF ≤ 40%), sPAP (43.1 ± 11.6 mmHg).. INTERVENTIONS:. All pts underwent successful TAVI using Edward-SAPIEN valve (71.2%) or Medtronic CoreValve (28.8%).. MAIN OUTCOME MEASURES:. Rates of mortality at 30 days, 6 months and 1 year were 2.8%, 11.2% and 17.5%.. RESULTS:. At 16-month follow up, 85.5% survived showing improved NYHA class (2.8 ± 0.6 vs 1.5 ± 0.7; p

Cancer vaccines are a real application of the extensive knowledge of immunology to the field of oncology. Tumors are dynamic complex systems in which several entities, events, and conditions interact among them resulting in growth, invasion, and metastases. The immune system includes many cells and molecules that cooperatively act to protect the host organism from foreign agents. Interactions between the immune system and the tumor mass include a huge number of biological factors. Testing of some cancer vaccine features, such as the best conditions for vaccine administration or the identification of candidate antigenic stimuli, can be very difficult or even impossible only through experiments with biological models simply because a high number of variables need to be considered at the same time. This is where computational models, and, to this extent, immunoinformatics, can prove handy as they have shown to be able to reproduce enough biological complexity to be of use in suggesting new experiments. Indeed, computational models can be used in addition to biological models. We now experience that biologists and medical doctors are progressively convinced that modeling can be of great help in understanding experimental results and planning new experiments. This will boost this research in the future.

"Introduction: H1N1 influenza can cause severe acute lung injury (ALI). Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients failing conventional mechanical ventilation, but its role is still controversial. We conducted a systematic review and meta-analysis on ECMO for H1N1-associated ALI. Methods: CENTRAL, Google Scholar, MEDLINE/PubMed and Scopus (updated 2 January 2012) were systematically searched. Studies reporting on 10 or more patients with H1N1 infection treated with ECMO were included. Baseline, procedural, outcome and validity data were systematically appraised and pooled, when appropriate, with random-effect methods. Results: From 1,196 initial citations, 8 studies were selected, including 1,357 patients with confirmed/suspected H1N1 infection requiring intensive care unit admission, 266 (20%) of whom were treated with ECMO. Patients had a median Sequential Organ Failure Assessment (SOFA) score of 9, and had received mechanical ventilation before ECMO implementation for a median of two days. ECMO was implanted before inter-hospital patient transfer in 72% of cases and in most patients (94%) the veno-venous configuration was used. ECMO was maintained for a median of 10 days. Outcomes were highly variable among the included studies, with in-hospital or short-term mortality ranging between 8% and 65%, mainly depending on baseline patient features. Random-effect pooled estimates suggested an overall in-hospital mortality of 28% (95% confidence interval 18% to 37%; I-2 = 64%). Conclusions: ECMO is feasible and effective in patients with ALI due to H1N1 infection. Despite this, prolonged support (more than one week) is required in most cases, and subjects with severe comorbidities or multiorgan failure remain at high risk of in-hospital death."

Revolutions in biotechnology and information technology have produced enormous amounts of biomedical data. Processing and analysis of these data are accelerating the expansion of our knowledge of biological systems. These advances are changing the way biomedical research, development, and applications are done. Clinical data complement the basic biology data, enabling detailed descriptions and modeling of various healthy and diseased states, disease progression, and the responses to therapies. The availability of data representing various biological states, processes, and their time dependencies enables the study of biological systems at various levels of organization, from molecule to whole organism, and even at population levels. Multiple sources of data support a rapidly growing body of biomedical knowledge; however, our ability to analyze and interpret these data lags far behind data generation and storage capacity. Computational models are increasingly used to help interpret biomedical data produced by high-throughput genomics, proteomics, and immunomics projects [1–3]. Advanced applications of computer models that enable the simulation of biological processes are used to generate hypotheses and plan experiments [4–7]. Appropriately interfaced with biomedical databases, computational models enable rapid access to higher-level knowledge and its sharing through data mining and knowledge discovery approaches. In this special issue, we take an interest in the investigation of the physiology and pathology of the immune responses, particularly the cellular and molecular processes. The paper contributed by R. Carvalho et al. presents an approach in which a computational model represents the interaction of mycobacterium infection with the innate immune system in zebrafish. They use the Petri Net formalism to model interaction between key host elements involved in granuloma formation and infection dissemination, defining a qualitative model for the understanding and description of causal relations within this dynamic process. Their systems in biology framework incorporates mathematical modeling to generate and test hypotheses, to perform virtual experiments, and to make experimentally verifiable predictions. This work demonstrates the use of mathematical models that support the study of mechanisms of tuberculosis infection. The immune system is able to respond more vigorously to the secondary contact with a given antigen than to the priming contact. Vaccination protocols generally include at least two doses, in order to obtain high antibody titers. In particular, studies performed in transgenic mouse models of Alzheimer's disease have demonstrated that antibodies against beta-amyloid are able to reduce plaques and improve cognition. In mouse models as well as in clinical trials in Alzheimer's disease patients, induction of high titers of anti-beta-amyloid antibodies correlates with the therapeutic efficacy of vaccination. F. Castiglione et al. have analyzed relations between the time elapsed from the first dose (priming) and the second dose (boost) on the antibody titers, coupling in vivo experiments with computer simulations to asses the effect of delaying the second injection. A major challenge in immunology is the translation of data into knowledge given the inherent complexity and dynamics of human physiology. The physiology and engineering communities have rich histories in applying computational approaches to translate data obtained from complex systems into knowledge of system behavior. J. Klinke II and Q. Wang review how two related engineering concepts, specifically prototyping and “fitness for use,” can be applied to overcome the pressing challenge in translating data into higher-level knowledge of basic immunology for use in practical applications, such as improvement of therapies. These concepts are illustrated using two immunology-related examples: behavior of beta cell mass at the onset of type 1 diabetes and the dynamics of dendritic cells in the lung. M. Pennisi presents a mathematical model developed to reproduce the immune response entitled with the combined administration of activated OT1 cytotoxic T lymphocytes (CTLs) and AntiCD137 monoclonal antibodies. This treatment is directed against melanoma in B16 OVA mouse models exposed to a specific immunotherapy strategy. In this paper, two compartments have been modeled: the injection point compartment where the treatment is administered and the skin compartment where melanoma tumor cells proliferate. The outcomes of the mathematical model are in good agreement with the in vivo results. In particular the sensitivity analysis highlighted the key role of OT1 CTLs and suggests that a possible reduction of the number of injected antibodies should not affect substantially the treatment efficacy. Bacterial infections can be acute or chronic. The chronic bacterial infections are characterized by a large bacterial load or by an infection where bacteria grow rapidly. In these cases the immune response is not capable of completely eliminating the infection, leading to the formation of a pattern known as microabscess (or abscess). The microabscess is characterized by an area comprising fluids, bacteria, immune cells (mainly neutrophils), and many types of dead cells. This distinct pattern of formation can only be numerically reproduced and studied by models that capture the spatio-temporal dynamics of the human immune system. B. Pigozzo et al. developed and implemented a computational model to study the process of microabscess formation during bacterial infection. Cats infected with the feline immunodeficiency virus (FIV) develop an acquired immunodeficiency syndrome (AIDS), similarly to humans infected with HIV. FIV infection causes an acute viremia, which decreases after several weeks, and the appearance of a subpopulation of activated CD8+ T cells that we refer to as CD8βlow cells. The expansion of this activated T cell population is recognized as an important marker of FIV infection and disease. Characterization of the CD8βlow population's complex pattern of expansion, including its correlation with other disease markers such as viral load, is likely to increase researchers' understanding of FIV infection and AIDS pathogenesis. B. Ribba et al. propose two simple independent mathematical equations to analyze the time evolution of CD8βlow population size and of viral load during primary infection in cats with FIV. They developed the models using a population approach and mixed-effects regression techniques, based on repeated measurements in more than 100 cats infected with FIV. Molecular dynamics (MD) simulations have to be sufficiently long to draw reliable conclusions. However, no method exists to prove that a simulation has converged. In the paper contributed by W. Schreiner et al. a method named “lagged RMSD-analysis” is proposed to determine if an MD-simulation has provided a sufficiently precise model. The analysis is based on RMSD values between pairs of configurations separated by variable time intervals Dt. In summary, these contributions present state of the art modeling of the immune system. The research papers appearing in this special issue will serve as a guide to current developments and a guide to emerging applications in the fascinating field of immune system modeling. Ultimately, the utility of computational/mathematical and other quantitative approaches will help provide better healthcare. The seven papers in this volume demonstrate various aspects of modeling of immune processes and preclinical studies of immune responses. Francesco Pappalardo Vladimir Brusic Holger Frohlich

On November 2009, the Italian health authorities set up a network of selected intensive care unit (ICU) centers (ECMOnet) to prepare for the treatment of the sickest patients of influenza A (H1N1) by means of extracorporeal membrane oxygenation (ECMO). To quickly and efficaciously train all the physicians working in the ICUs of the ECMOnet on ECMO use, we decided to take advantages of the opportunity provided by simulation technology. Simulation proved efficacious in providing adequate training and education to participants as confirmed by the survival results obtained by the group of ICUs of the ECMOnet. Our experience supports the use of simulation as a valuable alternative to animal laboratory sessions proposed by traditional ECMO training programs providing participants with cognitive, technical, and behavioral skills and allowing a proficient transfer of those skills to the real medical domain. Copyright © 2012 Society for Simulation in Healthcare.

Pulmonary vein stenosis after radiofrequency ablation occurs up to 3% and requires prompt diagnosis and treatment. Since clinical presentation is variable, a multimodality imaging approach currently provides an essential framework to address the diagnosis and appropriate treatment. A 40-year-old woman who had undergone surgical correction of sinus venosus atrial septal defect and partial anomalous pulmonary vein return required …