Neurocognitive function in procedures correcting severe aortic valve stenosis: patterns and determinants.

Background: Neurocognitive changes occurring after a surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) procedure for the correction of severe aortic stenosis (AS) have not been widely addressed and, if addressed, have produced conflicting results. The purpose of this study is to identify the pre-procedural neurocognitive pattern and its determinants in a setting of elderly (>65 years) patients with severe AS undergoing SAVR or TAVI and the changes occurring at a 2-3 month follow-up. Methods: This was a prospective cohort study included in the Italian Registry on Outcomes in Aortic Stenosis Treatment in Elderly Patients. Patients were assessed both before and after (2-3 months) the procedure using the Montreal Cognitive Assessment (MoCA) test. Data on periprocedural demographics, clinical factors, and outcome measures were collected. Results: Before the procedure, 70% of the patients demonstrated a MoCA score <23 points, which was indicative of cognitive dysfunction. The factors associated with neurocognitive dysfunction were age, functional capacity, chronic heart failure, and hemoglobin levels. After the procedure, there was an overall improvement in the MoCA score of the patients, but 28% of the patients showed a reliable worsening of their condition. The factors associated with MoCA worsening were platelet transfusions and the amount of red blood cell units transfused. Conclusion: The correction of severe AS leads to an improvement in neurocognitive function after 2-3 months. This improvement does not differentiate between SAVR and TAVI after matching for pre-procedural factors. The only modifiable factor associated with pre-procedural neurocognitive function is anemia, and anemia correction with red blood cell transfusions is associated with a worsening of neurocognitive function. This leads to the hypothesis that anemia correction before the procedure (with iron and/or erythropoietin) may limit the risk of a post-procedural worsening of neurocognitive function.

Sensitivity of serology assay in Covid-19 diagnosis: does the antigen matter?

Since the spreading of Sar-CoV-2 in March 2020, many serologic tests have been developed to identify antibody responses. Indeed, different commercial kits are directed against different antigens and could utilise different methods thereby triggering confusion and criticism. Here, we compared two Food and Drug Administration (FDA)-approved automatized assays that detect IgG responses against spike or nucleocapsid protein of Sars-Cov-2 virus in 127 subjects among healthcare workers of IRCCS Policlinico San Donato (MI), Italy. We observed different kinetics of IgG responses, demonstrating the importance of timing of sampling to correctly interpret the results both for infection diagnosis and for epidemiologic studies. We observed that Anti-N response starts earlier than Anti-S1/S2 response but also decreases earlier, affecting the sensitivity of the tests at different time points. Combining two different assays, designed against different antigens, could reduce false negative results. Finally, we observed a patient who produced anti-nucleocapsid IgG, but not anti-spike IgG. In conclusion, we investigated antibody responses in Covid-19 disease, aiming to direct clinicians and laboratory scientists to correctly interpret serologic results by always paying attention to clinical history correlation, timing of sampling, methods and antigens used, to avoid false negative results and obtain relevant epidemiologic data.

A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients.

Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg-1 . This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg-1 ) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.

The role of fibrinogen and fibrinogen concentrate in cardiac surgery: an international consensus statement from the Haemostasis and Transfusion Scientific Subcommittee of the European Association of Cardiothoracic Anaesthesiology.

To date, data regarding the efficacy and safety of administering fibrinogen concentrate in cardiac surgery are limited. Studies are limited by their low sample size and large heterogeneity with regard to the patient population, by the timing of fibrinogen concentrate administration, and by the definition of transfusion trigger and target levels. Assessment of fibrinogen activity using viscoelastic point-of-care testing shortly before or after weaning from cardiopulmonary bypass in patients and procedures with a high risk of bleeding appears to be a rational strategy. In contrast, the use of Clauss fibrinogen test for determination of plasma fibrinogen level can no longer be recommended without restrictions due to its long turnaround time, high inter-assay variability and interference with high heparin levels and fibrin degradation products. Administration of fibrinogen concentrate for maintaining physiological fibrinogen activity in the case of microvascular post-cardiopulmonary bypass bleeding appears to be indicated. The available evidence does not suggest aiming for supranormal levels, however. Use of cryoprecipitate as an alternative to fibrinogen concentrate might be considered to increase plasma fibrinogen levels. Although conclusive evidence is lacking, fibrinogen concentrate does not seem to increase adverse outcomes (i.e., thromboembolic events). Large prospective multi-centre studies are needed to better define the optimal perioperative monitoring tool, transfusion trigger and target levels for fibrinogen replacement in cardiac surgery.

Body mass index stratification in hospitalized Italian adults with congenital heart disease in relation to complexity, diagnosis, sex and age.

BACKGROUND AND AIMS: Adults with congenital heart disease (ACHD) are at risk of overweight and obesity, two major health problems, though underweight can be a negative prognostic factor too. Awareness of the body mass index (BMI) in ACHD is very limited. The present study describes the use and prevalence of BMI in Italian symptomatic hospitalized ACHD patients in relation to complexity by Bethesda system classification, diagnosis, sex and age. METHODS AND RESULTS: We classified 1388 ACHD patients, aged 18-69 years, on the basis of their BMI, and compared them to the Italian reference population. In our total ACHD population we found a significantly higher prevalence of underweight compared to the Italian reference population (6.34% vs 3.20%). ACHD women were more underweight than men. Underweight decreased with age. Overweight was significantly less frequent in the total ACHD population (26.73% compared to 31.70%) in the Italian reference population. Men were more likely to be overweight than women. In statistical terms obesity was similar in the Italian reference population (10.50%) and our ACHD population (9.58%). Both overweight and obesity increased with age. Results were comparable using a diagnostic anatomical-functional classification and the Bethesda system classification. CONCLUSIONS: In our cohort of ACHD the prevalence of underweight was double that of the Italian reference population. The prevalence of overweight was lower, while obesity was similar. Since BMI does not account for differences in body fat distribution, a future aim will be to quantify the visceral component of the adipose tissue in ACHD patients and examine their body composition in order to reflect their risk of acquired cardiovascular disease better, and either to maintain or achieve an adequate visceral component.

Early or late fresh frozen plasma administration in newborns and small infants undergoing cardiac surgery: the APPEAR randomized trial.

BACKGROUND: In newborns and small infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) and blood priming, it is unclear whether there is reduced blood loss if fresh frozen plasma (FFP) is added to the CPB priming volume. This single-centre, randomized trial tested the hypothesis that the administration of FFP after CPB (late FFP group) is superior to FFP priming (early FFP group) in terms of postoperative bleeding and overall red blood cell (RBC) transfusion. METHODS: Seventy-three infants weighing <10 kg were randomly allocated to receive FFP to supplement RBCs in the CPB priming solution ( n =36) or immediately after CPB ( n =37). The primary endpoint was a difference in postoperative blood loss; secondary endpoints included the amount of RBCs and FFP transfused through the first 48 postoperative hours. RESULTS: All patients were included in the analysis. Patients in the late FFP arm had greater postoperative mean blood loss than patients in the early FFP arm [33.1 ( sd 20.6) vs 24.1 (12.9) ml kg -1 ; P =0.028], but no differences in transfusions were found. The subgroup of cyanotic heart disease patients had comparable results, but with greater use of RBCs in the late FFP group. CONCLUSIONS: In infants undergoing cardiac surgery, FFP in the priming solution appears slightly superior to late administration in terms of postoperative bleeding. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov , NCT02738190.

Microcirculatory changes in children undergoing cardiac surgery: a prospective observational study.

BACKGROUND: The effects of cardiac surgery on the microcirculation of children are unknown. The aim of this study was to assess the microcirculatory changes in children undergoing surgery for correction of congenital heart disease. METHODS: We used a videomicroscope (Sidestream Dark Field, SDF) in a convenience sample of 24 children

Desmopressin after cardiac surgery in bleeding patients. A multicenter randomized trial.

BACKGROUND: Previous studies showed that desmopressin decreases post-operative blood loss in patients undergoing cardiac surgery. These studies were small and never studied the effect of desmopressin in patients with active bleeding. Objective of the study was to determine whether desmopressin reduces red blood cells transfusion requirements in patients with active bleeding after cardiac surgery who had been pre-treated with tranexamic acid. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized elective patients with bleeding after cardiac surgery despite pre-treatment with tranexamic acid, to receive placebo (saline solution) or a single administration of desmopressin (0.3 µg/kg in saline solution). The primary endpoint was the number of patients requiring red blood cells transfusion after randomization and during hospital stay. Secondary end points were: blood loss from chest tubes during the first 24 h after study drug administration, hours of mechanical ventilation, intensive care unit stay, and in-hospital mortality. RESULTS: The study was interrupted after inclusion of 67% of the planned patients for futility. The number of patients requiring red blood cells transfusion after randomization was 37/68 (54%) in desmopressin group and 33/67 (49%) in placebo group (P = 0.34) with no difference in blood loss: 575 (interquartile 422-770) ml in desmopressin group and 590 (476-1013) ml in placebo group (P = 0.42), mechanical ventilation, intensive care unit stay or mortality. CONCLUSIONS: This multicenter randomized trial demonstrated that, in patients pre-treated with tranexamic acid, desmopressin should not be expected to improve treatment of patients who experience bleeding after cardiac surgery.

Fibrinogen supplementation after cardiac surgery: insights from the Zero-Plasma trial (ZEPLAST).

BACKGROUND: Fibrinogen supplementation has been proposed both to prevent and treat postoperative bleeding in cardiac surgery. The optimal fibrinogen concentration trigger and target values and the fibrinogen concentrate dose required remain uncertain. This subanalysis of data from the Zero-Plasma Trial (ZEPLAST) assessed target fibrinogen values and the corresponding fibrinogen concentrate dose for supplementation. METHODS: We performed a post hoc analysis of 116 subjects included in the randomized, placebo-controlled ZEPLAST trail. Data considered were fibrin-based thromboelastometry (FIBTEM) maximum clot firmness (MCF) determined by whole-blood thromboelastometry (ROTEM) before and after placebo or fibrinogen concentrate, Clauss fibrinogen concentration after placebo or fibrinogen concentrate, postoperative bleeding and severe bleeding (SB). The association between FIBTEM MCF and Clauss fibrinogen concentration was tested with linear regression analyses. The predictive value for SB of FIBTEM MCF and Clauss fibrinogen concentration was tested with receiver operating characteristic analyses. RESULTS: There was a good association between FIBTEM MCF and Clauss fibrinogen concentration in the baseline study population (r(2) = 0.66), which worsened in fibrinogen-supplemented subjects. Both FIBTEM MCF and Clauss fibrinogen concentration yielded a good discriminative power for SB (area under the curve 0.721 and 0.767, respectively). The negative predictive value for SB was 100% for a Clauss fibrinogen concentration of 287 mg dl(-1) and 98% for an FIBTEM MCF of 14 mm. Based on these newly defined target values, the dose of fibrinogen concentrate needed would be 3 g lower than the dose used in ZEPLAST. CONCLUSIONS: A dose of fibrinogen concentrate rarely exceeding 2 g might be sufficient to prevent bleeding in cardiac surgery.

Moderate-degree acidosis is an independent determinant of postoperative bleeding in cardiac surgery.

BACKGROUND: Acidosis is a well-known factor leading to coagulopathy. It has been widely explored as a risk factor for severe bleeding in trauma patients. However, no information with respect to acidosis as a determinant of postoperative bleeding in cardiac surgery patients exists. The aim of this study was to investigate the role of acidosis and hyperlactatemia (HL) in determining postoperative bleeding and need for surgical revision in cardiac surgery patients. METHODS: We carried out a retrospective analysis on 4521 patients receiving cardiac operations in two institutions. For each patient the preoperative data and operative profile was available. Arterial blood gas analysis data at the arrival in the intensive care unit were analyzed to investigate the association between acidosis (pH<7.35), HL (>4.0 mMol/L) and postoperative bleeding and surgical revision rate. RESULTS: After correction for the potential confounders, both acidosis (P=0.001) and HL (P=0.001) were significantly associated with the amount of postoperative bleeding. HL was an independent risk factor for postoperative bleeding even in absence of acidosis. Overall, surgical revision rate was 5.6% in patients with HL and no acidosis; 7.7% in patients with acidosis and HL, and 7.2% in patients with acidosis and no HL. All these values are significantly (P=0.001) higher than the ones in patients without acidosis/HL (2%). CONCLUSIONS: Even a moderate degree of postoperative acidosis is associated with a greater postoperative bleeding and surgical revision rate in cardiac surgery patients. Correction of acidosis with bicarbonate does not lead to an improvement of the postoperative bleeding asset.

Risk scores to facilitate preoperative prediction of transfusion and large volume blood transfusion associated with adult cardiac surgery.

BACKGROUND: The aim of this study was to develop two novel risk prediction scores for transfusion and bleeding that would be used to inform treatment decisions, quality assurance, and clinical trial design in cardiac surgery. METHODS: Clinical data prospectively collected from 26 UK cardiac surgical centres and a single European centre were used to develop two risk prediction models: one for any red blood cell (RBC) transfusion, and the other for large volume blood transfusion (≥4 RBC units; LVBT), an index of severe blood loss. 'Complete case' data were available for 24 749 patients. Multiple imputation was used for missing covariate data (typically <5% per variable), with the imputed data set containing 39 970 patients. Risk models were developed in the complete case data set, with internal validation using leave-one-centre-out cross-validation. The final selected models were fitted to the imputed data set. Final risk scores were then compared with the performance of three existing scores: the Transfusion Risk and Clinical Knowledge score (TRACK), the Transfusion Risk Understanding Scoring Tool (TRUST), and the Papworth Bleeding Risk Score (BRiSc). RESULTS: The area under the receiver operating characteristic curve (AUC) was 0.77 (95% confidence interval 0.77-0.77) for the any RBC transfusion score and AUC 0.80 (0.79-0.80) for the LVBT score in the imputed data set. The LVBT model also showed excellent discrimination (Hosmer-Lemeshow P=0.32). In the imputed data set, the AUCs for the TRACK and TRUST scores for any RBC transfusion were 0.71 and 0.71, respectively, and for LVBT the AUC for the BRiSc score was 0.69. CONCLUSIONS: Two new risk scores for any RBC transfusion or LVBT among cardiac surgery patients have excellent discrimination, and could inform clinical decision making.

Pre-operative fibrinogen supplementation in cardiac surgery patients: an evaluation of different trigger values.

BACKGROUND: Pre-operative fibrinogen levels are negatively associated with postoperative bleeding in cardiac surgery patients. The guidelines of the European Society of Anaesthesiology consider the possibility of a prophylactic pre-operative supplementation in patients with fibrinogen levels<`3.8 g/l. The present study is a reanalysis of published data aimed to define the diagnostic accuracy of different values of pre-operative fibrinogen levels in predicting severe post-operative bleeding. METHODS: Data were retrieved for 2154 patients in four different studies. Severe bleeding (SB) was defined as a post-operative chest drain output>1 l/12 h. Diagnostic accuracy for prediction of SB was tested at three cutoff values of pre-operative fibrinogen (2.5 g/l, 3.0 g/l, and 3.8 g/l). RESULTS: At all the three cutoff values, pre-operative fibrinogen levels had an excellent negative predictive value, ranging from 86% to 100%. Conversely, the positive predictive value was poor at all the cutoff levels: 12% (3.8 g/l), 14% (3.0 g/l), and 19% (2.5 g/l). Overall, the accuracy of pre-operative fibrinogen levels for the prediction of SB was poor. A strategy based on pre-operative fibrinogen supplementation would lead to inappropriate treatment in > 80% of the treated patients. Overall, a trigger value of 3.8 g/l would result in an inappropriate treatment in 52% of the patients, of 3.0 g/l in 20% of the patients, and of 2.5 g/l in 4% of the patients. CONCLUSION: Correction of pre-operative fibrinogen levels below 3.8 g/l would lead to an excessive rate of inappropriate interventions. Values below 2.5 g/l could be considered.

Effects of priming volume reduction on allogeneic red blood cell transfusions and renal outcome after heart surgery.

INTRODUCTION: Excessive hemodilution during cardiopulmonary bypass (CPB) is associated with an increased rate of red blood cell (RBC) transfusion and acute kidney injury (AKI). Minimization of the oxygenator priming volume is a measure to contain hemodilution. In this study, we evaluated the new oxygenator, Sorin Inspire 6™, with respect to its ability to limit hemodilution, RBC transfusion rate and postoperative AKI rate. METHODS: A retrospective study on a consecutive series of 1,724 adult patients receiving heart surgery with CPB. Patients treated with the Inspire 6™ were assigned to the low priming volume oxygenator (LPVO) group (N=383) and patients treated with conventional oxygenators to the conventional group (N=1,341). Dynamic priming volume, time course of the hematocrit, RBC transfusions and AKI rate were compared between the groups. RESULTS: Priming volume was significantly (p=0.001) lower in the LPVO group (624±113 mL) vs. the conventional group (775±150 mL), with higher values of hematocrit during and after CPB. After correction for other confounders, patients in the LPVO group had a significantly lower RBC transfusion rate (odds ratio 0.68, 95% confidence interval 0.52-0.90, p=0.006) and AKI rate (odds ratio 0.55, 95% confidence interval 0.32-0.93, p=0.032). CONCLUSION: The Inspire 6™ oxygenator allows a significant containment of hemodilution during CPB, reducing the risk of RBC transfusions and postoperative AKI.

Effect of preoperative P2Y12 and thrombin platelet receptor inhibition on bleeding after cardiac surgery.

BACKGROUND: Drugs that act on the platelet P2Y12 receptor are responsible for postoperative bleeding in cardiac surgery. However, protease-activated receptor (PAR) that reacts to thrombin stimulation might still be active in patients treated with P2Y12 inhibitors. Preoperative platelet function testing could possibly guide the timing of surgery. We investigated the association between P2Y12 receptor and PAR inhibition and bleeding after cardiac surgery. METHODS: A retrospective cohort study of 361 patients undergoing cardiac surgery and treated with P2Y12 anti-platelet agents was undertaken. All patients received a preoperative multiplate electrode aggregometry testing of platelet P2Y12 receptor activity (ADPtest) and PAR reactivity with thrombin receptor-activating peptide (TRAP) stimulation. ADPtest and TRAPtest data measured before surgery were analysed for association with postoperative bleeding (ml per 12 h) and severe postoperative bleeding. RESULTS: Both the ADPtest and the TRAPtest were significantly (P=0.001) associated with postoperative bleeding. A threshold of 22 U for the ADPtest yielded a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 20%, and a threshold of 75 U for the TRAPtest yielded an NPV of 95% and a PPV of 23%. In the subgroup of patients with ADPtest <22 U, TRAPtest ≥75 U was not associated with severe bleeding (NPV of 100% and PPV of 37%). CONCLUSIONS: In patients taking P2Y12 receptor inhibitors, residual platelet reactivity to thrombin stimulation limits the risk of severe postoperative bleeding.

Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate.

BACKGROUND: We aimed to create a theoretical tool to model the effect of three haemostatic agents containing fibrinogen (therapeutic plasma, cryoprecipitate, and fibrinogen concentrate) on the patient's plasma fibrinogen level. METHODS: A mathematical model was developed step-wise. The relationship between the amount of haemostatic agent and plasma fibrinogen level was plotted for each agent. A fibrinogen concentration simulator (FCS(amount)) was developed, where the amount of haemostatic agent was calculated from patient characteristics, agent characteristics, and target plasma fibrinogen level. Refinements were introduced so that (i) FCS(amount) would account for in vivo fibrinogen recovery, (ii) circulatory volume would not increase ad infinitum with increasing amounts, and (iii) red blood cells would be included in the simulation if haematocrit decreased below a certain level. A second FCS (FCS(level)) was created to calculate fibrinogen levels resulting from specified amounts of haemostatic agents. RESULTS: Fibrinogen concentration in haemostatic agents has a critical impact on their ability to increase patients' fibrinogen levels. If the target plasma fibrinogen level approaches the concentration of the fibrinogen source, the required amounts increase exponentially; it is impossible to achieve a target above the concentration of the fibrinogen source. CONCLUSIONS: We successfully developed two theoretical tools answering the questions: 'How much therapeutic plasma, cryoprecipitate, or fibrinogen concentrate would be needed to achieve a specified target fibrinogen level?' and 'What would be the resultant fibrinogen level for a specified amount of haemostatic agent?' The current tools are not intended for clinical application, but they are potentially useful for educational purposes.