Bonizella Biagioli

Myocardial and lung injury after cardiopulmonary bypass: role of interleukin (IL)-10.

BACKGROUND Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8 play a key role in the inflammatory cascade after cardiopulmonary bypass (CPB) and may induce cardiac and lung dysfunction. Antiinflammatory cytokines such as IL-10 may also significantly limit these complications. Corticosteroid administration before CPB increases blood IL-10 levels and prevents proinflammatory cytokine release. This study examined the association of increased release of IL-10, stimulated by steroid pretreatment, with reduced myocardial and lung injury after CPB. METHODS Twenty patients undergoing coronary artery bypass grafting (CABG) received either preoperative steroid (n = 10, protocol group) or no steroid (n = 10, control group). Perioperative care was standardized, and all caregivers were blinded to treatment group. Seven intervals of blood samples were obtained and assayed for TNF-alpha, IL-6, IL-8, and IL-10. Various hemodynamic and pulmonary measurements were obtained perioperatively. Levels of MB isoenzyme creatine kinase (CK-MB) were also measured. RESULTS In the protocol group, proinflammatory cytokines were significantly reduced while IL-10 levels were much higher after CPB. The protocol group had a lower alveolar-arterial oxygen gradient and higher ratio of arterial oxygen pressure to fraction of inspired oxygen after CPB. Creatine kinase (CK) and CK-MB were reduced in the patients treated with steroid. Correlations were found between plasma cytokines levels and cardiac index, and CK-MB. CONCLUSIONS This study confirms that corticosteroids abolish proinflammatory cytokines release and increase blood IL-10 levels after CPB. Our findings demonstrate a greater release of IL-10 induced by steroid pretreatment, and better heart and lung protection after CPB.

Speckle tracking echocardiography as a new technique to evaluate right ventricular function in patients with left ventricular assist device therapy.

BACKGROUND Right ventricular (RV) systolic function has a critical role in determining the clinical outcome and the success of using left ventricular assist devices (LVADs) in patients with refractory heart failure. RV deformation analysis by speckle tracking echocardiography (STE) has recently allowed a deeper analysis of RV longitudinal function. The aim of the study was to observe RV function by STE in patients with advanced heart failure before and after LVAD implantation. METHODS Transthoracic echo Doppler was performed in 10 patients referred for LVAD therapy at baseline and with serial echocardiograms after LVAD implantation. In a sub-group of 4 patients, an echocardiographic evaluation was also made after intra-aortic balloon pump (IABP) support was initiated and before LVAD implantation. All echocardiographic images were analyzed off-line to calculate the free wall RV longitudinal strain (RVLS). RESULTS Three patients who presented the lowest free wall RVLS values at baseline, showed a progressive decline of RVLS after LVAD implant, presenting finally RV failure; however, patients with higher values of RVLS at baseline presented a further and overt increase of strain values in the course of follow-up. The overall performance for the prediction of RV failure after LVAD implant was greatest for free wall RVLS (area under the curve, 0.93). For the sub-group receiving the IABP as an intermediate step, only 2 patients with an increase of RVLS after IABP implantation also showed an increase of RVLS levels, after subsequent LVAD implantation. The 2 patients without an increase of RVLS after IABP implantation also presented with RV failure after LVAD therapy. CONCLUSIONS This study of 10 patients indicates that the new parameter of RVLS, representing RV myocardial deformation, may have important clinical implications for the selection and management of LVAD patients. A large multicenter study is required to confirm these observations and to quantify the clinical significance of changes in RVLS value.

Energetic myocardial metabolism and oxidative stress: let's make them our friends in the fight against heart failure.

Heart failure (HF) is a syndrome causing a huge burden in morbidity and mortality worldwide. Current medical therapies for HF are aimed at suppressing the neurohormonal activation. However, novel therapies are needed for HF, independent of the neurohormonal axis, that can improve cardiac performance and prevent the progression of heart dysfunction. The modulation of cardiac metabolism may represent a new approach to the treatment of HF. The healthy heart converts chemical energy stored in fatty acids (FA) and glucose. Utilization of FA costs more oxygen per unit of ATP generated than glucose, and the heart gets 60-90% of its energy for oxidative phosphorylation from FA oxidation. The failing heart has been demonstrated to be metabolically abnormal, in both animal models and in patients, showing a shift toward an increased glucose uptake and utilization. The manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less FA oxidation may improve ventricular performance and slow the progression of heart dysfunction. Impaired mitochondrial function and oxidative phosphorylation can reduce cardiac function by providing an insufficient supply of ATP to cardiomyocytes and by increasing myocardial oxidative stress. Although there are no effective stimulators of oxidative phosphorylation, several classes of drugs have been shown to open mitochondrial K(ATP) channels and, indirectly, to improve cardiac protection against oxidative stress. This article focuses on the energetic myocardial metabolism and oxidative status in the normal and failing heart, and briefly, it overviews the therapeutic potential strategies to improve cardiac energy and oxidative status in HF patients.

Cardiac surgery: myocardial energy balance, antioxidant status and endothelial function after ischemia–reperfusion

Myocardial and endothelial damage is still a widely debated problem during the ischemia-reperfusion sequence in heart surgery. We evaluated myocardial purine metabolites, antioxidant defense mechanisms, oxidative status and endothelial dysfunction markers in 14 patients undergoing coronary artery by-pass graft (CABG). Heart biopsies were taken before aortic cross-clamping (t1), before clamp removal (t2) and 30 min after reperfusion (t3); perchloric extracts of the tissue were analyzed for glutathione, NAD, nucleotide nucleoside and base content by capillary electrophoresis (CE). In plasma samples from the coronary sinus we evaluated: nitrate and nitrite concentrations by CE, plasma glutathione peroxidase (plGPx) by ELISA, endothelin-1 (ET-1) by RIA and reactive oxygen metabolites (ROM) by colorimetric assay. During the ischemic period (t2) we observed a reduction in cellular NAD and GSH levels, as well as nitrate, nitrite and plGPx. ATP and GTP levels decreased and their catabolic products AMP, GMP, IMP, adenosine, inosine and hypoxanthine accumulated. The energy charge, ATP/ADP ratio, and nucleotide/(nucleoside + base) ratios decreased. At t3, levels of plasma ET-1 increased and monophosphate nucleotides tended to return to basal values. The energy charge did not increase but the nucleotide/(nucleoside + nucleobase) ratio recovered to some extent. Levels of nitrates plus nitrites continued to decrease. No significant variation in ROM levels was observed. Our data indicate that oxidative stress and endothelial damage are major events during CABG, overwhelming the scavenging capacity of the myocyte and preventing restoration of the normal energy balance for 30 min after reperfusion. The AMP deaminase pathway leading to IMP production is active during ischemia and adenosine is not the main compound derived from ATP break-down in the human heart. The possible role of extracorporeal circulation is also discussed.

Predicting transfusions in cardiac surgery: the easier, the better: the Transfusion Risk and Clinical Knowledge score.

Background and Objectives  Allogeneic blood products transfusions are associated with an increased morbidity and mortality risk in cardiac surgery. At present, a few transfusion risk scores have been proposed for cardiac surgery patients. The present study is aimed to develop and validate a risk score based on adequate statistical analyses joint with a clinical selection of a limited (five) number of preoperative predictors.

Capillary electrophoresis in the evaluation of ischemic injury: simultaneous determination of purine compounds and glutathione.

An understanding of tissue energy metabolism and antioxidant status is of major interest in the field of organ preservation for transplantation. Nucleotide and glutathione are indicators of cell damage occurring during ischemia and reperfusion. A high performance capillary electrophoresis (HPCE) method with UV detection (185 nm) for the simultaneous analysis of intracellular free ribonucleotides, nucleosides, bases and glutathione (oxidized and reduced form) in myocardial tissues is described. The method does not involve thiol derivatization. The separations were carried out in an uncoated fused‐silica capillary, 60 cm long, 52.5 cm to detector, 75 μm ID, with 20 mM Na‐borate buffer, pH 10.00, at 20 kV voltage and reading at 185 nm. Injection was hydrostatic for 12 s and total analysis time was 20 min. The technique enables optimum separation of all the compounds examined and has a resolution similar to that of HPLC analysis, with the advantage of fast simultaneous measurement of cell nucleotide metabolism and redox state, not possible with HPLC.

Predictive role of pretransplant serum CXCL10 for cardiac acute rejection.

Background. The detection of acute rejection in heart transplantation remains an important feature of transplant management, especially in the early phase. Frequent surveillance with endomyocardial biopsy is necessary, even though it is an invasive procedure and carries a certain risk. Hence, noninvasive biomarkers able to predict acute rejection could be a further helpful tool in patient management. The interferon-&ggr;-inducible chemokine CXCL10 is required for initiation and development of graft failure caused by acute or chronic rejection. It has been reported that CXCL10 serum level is predictive of graft loss in kidney graft recipients. In the present study, we investigated whether pretransplant CXCL10 serum level may be a predictive noninvasive biomarker in heart transplant (HTx) recipients, as well. Methods. Sera from 143 patients undergoing orthotopic heart transplantation were collected before surgery and tested for CXCL10 and CCL22 and compared with serum samples from healthy subjects. Results. We found that basal CXCL10 serum levels in HTx recipients were significantly higher than in healthy subjects, whereas no difference was seen in CCL22 levels. Among HTx recipients, CXCL10 serum levels of rejectors were significantly higher than in nonrejectors. Our results showed that CXCL10 was a significant independent risk factor of several variables and had the highest predictive value for early acute heart rejection, with 160 pg/mL cutoff value. Conclusions. In HTx recipients, measurement of pretransplant CXCL10 serum levels could be a clinically useful tool for predicting cardiac acute rejection, especially in the early posttransplant period.

An adjusted EuroSCORE model for high-risk cardiac patients

OBJECTIVE To verify the accuracy and precision of the logistic European system for cardiac operative risk evaluation (EuroSCORE) in high-risk cardiac surgery patients and to develop and externally validate a new system of recalibration. METHODS The development series included 4279 high-risk patients who had undergone cardiac operations at the IRCCS Policlinico S. Donato. Performance, accuracy, and precision of the logistic EuroSCORE were assessed in this series, using a deciles-based comparison between expected and observed mortality rates, a receiver operating characteristic analysis, and a Hosmer-Lemeshow test for calibration. Differences between predicted and observed mortality rates were mathematically evaluated to develop an adjusted logistic EuroSCORE. This adjusted risk score was subsequently validated with the same approach on an external series of 1459 high-risk patients who had undergone cardiac operations at the Siena hospital. RESULTS The adjusted logistic EuroSCORE was based on five different correction factors applied to the crude logistic EuroSCORE depending on its value. At the external validation, this model provided a good performance, with observed mortality rates not significantly different from the expected in 8 out of 10 deciles of risk distribution. The adjusted EuroSCORE had the same moderate balanced accuracy of the crude logistic EuroSCORE (area under the curve: 0.695), with a better precision (Hosmer-Lemeshow calibration test: chi(2): 3.6, p=0.891). CONCLUSIONS Recalibration of the logistic EuroSCORE in high-risk patients is needed due to its tendency to overestimate the mortality risk. The application of a variable correction factor results in a better performance, increased precision, with unaltered balanced accuracy.

A comparative analysis of predictive models of morbidity in intensive care unit after cardiac surgery – Part I: model planning

BackgroundDifferent methods have recently been proposed for predicting morbidity in intensive care units (ICU). The aim of the present study was to critically review a number of approaches for developing models capable of estimating the probability of morbidity in ICU after heart surgery. The study is divided into two parts. In this first part, popular models used to estimate the probability of class membership are grouped into distinct categories according to their underlying mathematical principles. Modelling techniques and intrinsic strengths and weaknesses of each model are analysed and discussed from a theoretical point of view, in consideration of clinical applications.MethodsModels based on Bayes rule, k- nearest neighbour algorithm, logistic regression, scoring systems and artificial neural networks are investigated. Key issues for model design are described. The mathematical treatment of some aspects of model structure is also included for readers interested in developing models, though a full understanding of mathematical relationships is not necessary if the reader is only interested in perceiving the practical meaning of model assumptions, weaknesses and strengths from a user point of view.ResultsScoring systems are very attractive due to their simplicity of use, although this may undermine their predictive capacity. Logistic regression models are trustworthy tools, although they suffer from the principal limitations of most regression procedures. Bayesian models seem to be a good compromise between complexity and predictive performance, but model recalibration is generally necessary. k-nearest neighbour may be a valid non parametric technique, though computational cost and the need for large data storage are major weaknesses of this approach. Artificial neural networks have intrinsic advantages with respect to common statistical models, though the training process may be problematical.ConclusionKnowledge of model assumptions and the theoretical strengths and weaknesses of different approaches are fundamental for designing models for estimating the probability of morbidity after heart surgery. However, a rational choice also requires evaluation and comparison of actual performances of locally-developed competitive models in the clinical scenario to obtain satisfactory agreement between local needs and model response. In the second part of this study the above predictive models will therefore be tested on real data acquired in a specialized ICU.

Systemic arterial waveform analysis and assessment of blood flow during extracorporeal circulation

Background: The pressure recording analytical method (PRAM) is a method for real-time beat-to-beat quantification of peripheral blood flow based on the analysis of arterial waveform morphology. Since PRAM can be implemented in any conditions of flow, whether physiological or artificial, we assessed its accuracy in patients undergoing cardiac surgery during extracorporeal circulation (ECC), using the roller-pump device as the reference gold standard. Methods: We prospectively studied 32 patients undergoing elective coronary surgery. Flow values obtained by PRAM from the radial artery were compared with simultaneous values by thermodilution in physiological conditions of flow and with the roller-pump device readings during ECC. Results: Before and after ECC, the overall estimates of flow measured by PRAM closely agreed with thermodilution (mean difference 0.07±0.40 L/min). During ECC, PRAM estimates of flow also closely correlated with simultaneous pump readings (mean difference 0.11±0.33 L/min). At time of weaning from ECC, two patterns of hemodynamic adaptation were documented by PRAM following resumption of cardiac contraction: in most patients (n = 26; 80%), cardiac output (CO) was stable (reduction ≤ 10% compared to the steady ECC phase); six patients (20%) showed a fall in CO exceeding 10% and up to 38%. Conclusions: PRAM provided accurate, continuous quantification of peripheral blood flow during each phase of cardiac surgery, including ECC, and allowed early recognition of patients with low CO during weaning from the pump.