Tiziano Menon

Polarizing microplegia improves cardiac cycle efficiency after CABG for unstable angina.

BACKGROUND Myocardial protection during coronary artery bypass grafting (CABG) for unstable angina (UA) still represents a major challenge, ought to the risk for further ischemia/reperfusion injury. Few studies investigate the biochemical, hemodynamic and echocardiographic results of microplegia (Mic) in UA. METHODS Eighty UA-patients undergoing CABG were randomized to Mic (Mic-Group) or standard 4:1 blood Buckberg-cardioplegia (Buck-Group). Troponin-I and lactate were sampled from coronary sinus at reperfusion (T1), and from peripheral blood preoperatively (T0), at 6 (T2), 12 (T3) and 48 (T4) hours. Cardiac index (CI), indexed systemic vascular resistances (ISVR), Δp/Δt, cardiac cycle efficiency (CCE), and central venous pressure (CVP) were collected preoperatively (T0), and since Intensive Care Unit (ICU)-arrival (T1) to 24h (T5). Echocardiographic E-wave (E), A-wave (A), E/A, peak early-diastolic TDI-mitral annular-velocity (Ea), and E/Ea investigated the diastolic function and Wall Motion Score Index (WMSI) the systolic function, preoperatively (T0) and at 96h (T1). RESULTS Mic-Group showed lower troponin-I and lactate from coronary sinus (p=.0001 for both) and during the postoperative course (between-groups p=.001 and .0001, respectively). WMSI improved only after Mic (time-p=.001). Higher CI Δp/Δt and CCE (between-groups p=.0001), with comparable CVP and ISVR (p=N.S.) were detected after Mic. Diastolic function improved in both groups, but better after Mic (between-groups p=.003, .001, and .013 for E, E/A, and Ea, respectively). Mic resulted in lower transfusions (p=.006) and hospitalization (p=.002), and a trend towards lower need/duration of inotropes (p=.04 and p=.041, respectively), and ICU-stay (p=.015). CONCLUSION Microplegia attenuates myocardial damage in UA, reduces transfusions, improves postoperative systo-diastolic function, and shortens hospitalization.

Preservation of Endothelium Nitric Oxide Release by Pulsatile Flow Cardiopulmonary Bypass When Compared With Continuous Flow

The aim of this work is to analyze endothelium nitric oxide (NO) release in patients undergoing continuous or pulsatile flow cardiopulmonary bypass (CPB). Nine patients operated under continuous flow CPB, and nine patients on pulsatile flow CPB were enrolled. Plasma samples were withdrawn for the chemiluminescence detection of nitrite and nitrate. Moreover the cellular component was withdrawn for the detection of nitric oxide synthase (NOS) activity in the erythrocytes, and an estimation of systemic inflammatory response was carried out. Significant reduction in the intraoperative concentration with respect to the preoperative was observed only under continuous flow CPB for both nitrite and NO(x) (nitrite + nitrate) concentration (P = 0.010 and P = 0.016, respectively). Significant difference in intraoperative nitrite concentration was also observed between the groups (P = 0.012). Finally, erythrocytes showed a certain endothelial NOS activity, which did not differ between the groups, and no differences in the inflammatory response were pointed out. The significant reduction of NO(2)(-) concentration under continuous perfusion revealed the strong connection among perfusion modality, endothelial NO release, and plasmatic nitrite concentration. The similar erythrocyte eNOS activity between the groups revealed that the differences in blood NO metabolites are mainly ascribable to the endothelium release.

Selective pulmonary pulsatile perfusion with oxygenated blood during cardiopulmonary bypass attenuates lung tissue inflammation but does not affect circulating cytokine levels

OBJECTIVE Improved respiratory outcome has been shown after selective pulsatile pulmonary perfusion (sPPP) during cardiopulmonary bypass (CPB). No contemporary study has analysed the impact of sPPP on alveolar and systemic inflammatory response in humans. METHODS Sixty-four patients undergoing a coronary artery bypass graft (CABG) were randomized to sPPP or standard CPB (32 patients each). An alveolar-arterial oxygen gradient (A-aDO(2)) was measured preoperatively (T0), at ICU arrival (T1), 3 h postoperatively (T2) and postextubation (T3). The bronchoalveolar lavage (BAL) was collected at T0, T1 and T2. White blood cells (WBCs), neutrophils, mononucleates and lymphocytes in BAL infiltrates were compared between the two groups. A cytokine assay for interleukin-1 (IL-1), IL-8, tumour necrosis factor alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), growth regulated oncogene-alpha (GRO-α) and interferon (IFN)-γ was collected from the BAL and peripheral blood at the same time-points. Repeated-measure analysis of variance and non-parametric statistics were used to assess the between-group and during time differences. RESULTS The two groups proved comparable for perioperative variables. A-aDO(2) proved better after sPPP (group-P = 0.0001; group time-P < 0.0001). BAL infiltrates after sPPP showed lower WBCs, neutrophils and lymphocytes (group-P = 0.0001, group time-P = 0.0001 for all) together with higher mononucleates (group-P = 0.0001, group time-P = 0.0001). Proinflammatory cytokines and chemokine MCP-1 were lower in BAL after sPPP (group-P = 0.005, 0.034, 0.036 and 0.005, and group time-P = 0.001, 0.009, 0.001 and 0.0001 for IL-1, IL-8, TNF-α and MCP-1, respectively), whereas the immune modulator IFN-γ significantly augmented after sPPP (time-P = 0.0001) but remained stable after the standard CPB (time-P = 0.101, group-P = 001, group time-P = 0.0001). Indeed, serum cytokines were not different in the two groups during the study (P = NS at single time-points and as a function of time). CONCLUSIONS sPPP attenuates alveolar inflammation, as demonstrated by the lower neutrophilic/lymphocytic alveolar infiltration, and the secretion of anti-inflammatory rather than proinflammatory mediators.

Pulsatile cardiopulmonary bypass and renal function in elderly patients undergoing aortic valve surgery

OBJECTIVES To evaluate if pulsatile cardiopulmonary bypass (CPB) has any protective influence on renal function in elderly patients undergoing aortic valve replacement (AVR). METHODS Forty-six patients (≥ 75 years old) with aortic valve stenosis underwent AVR with either pulsatile perfusion (PP) or non-pulsatile perfusion (NP) during CPB. Haemodynamic efficacy of the blood pump during either type of perfusion was described in terms of the energy equivalent pressure and the surplus haemodynamic energy. Urine samples were collected before surgery, at sternum closure, and at 2 and 18 h of intensive care unit stay to detect acute kidney injury markers. Perioperative urine levels of N-acetyl-β-D-glucosaminidase (NAG), kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin (NGAL) were assessed together with plasma creatinine, creatinine clearance (CCr) and 24-h haemodynamic monitoring. Normally distributed continuous variables were described as mean ± standard deviation and non-normally distributed data were presented as the median [25th-75th percentiles]. RESULTS PP was characterized by a significantly higher amount of surplus haemodynamic energy transferred to the patients (P < 0.001), with lower mean systemic vascular resistance during CPB (P = 0.020) and during 18 h postoperatively (group-P = 0.018). No difference was found between pre- and postoperative CCr in the PP group (71 ± 23 vs 60 ± 35 ml/min, P = 0.27), while its statistically significant perioperative decrement was observed in the NP group (67 ± 24 vs 45 ± 15 ml/min, P < 0.001). The PP group showed significantly lower urinary levels of NAG at 18 h postoperatively (P = 0.008), and NGAL at sternum closure (P = 0.010), 2 h (P < 0.001) and 18 h (P = 0.015) postoperatively. CONCLUSIONS Short-term PP in elderly patients showed higher safety for renal physiology than NP, resulting in better maintenance of glomerular filtration and lower renal tissue injury.

Cardioprotective effect of δ-opioid receptor agonist vs. mild therapeutic hypothermia in a rat model of cardiac arrest with extracorporeal life support.

BACKGROUND To compare the effect of δ-opioid receptor agonist, d-Ala2-d-Leu5 enkephalin (DADLE) with normothermic control and therapeutic hypothermia on post resuscitation myocardial function in a model of extracorporeal life support (ECLS). METHODS Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32 °C) and DADLE intravenous infusion (1 mg/kg/h). Cooling to 32 °C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS. RESULTS DADLE administration resulted in a significantly enhanced recovery of LV systolic function expressed by slope of the LV end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than hypothermia and normothermia. LV stiffness indicated by end-diastolic pressure volume relationship (EDPVR) was significantly lower after DADLE administration (P<0.01). LV relaxation described by Tau was preserved after DADLE treatment but not after normothermia or mild hypothermia (P<0.01). Plasma lactate concentrations were lower in DADLE group (P<0.05). DADLE and not conventional hypothermia significantly increased phosphorylation of the kinases ERK1 and 2 (3.9±0.3 and 3.1±0.5 vs. 0.4±0.1 and 0.3±0.1-fold of baseline levels) (P<0.001). Both DADLE and hypothermia but not normothermia increase phosphorylation of Akt. CONCLUSIONS DADLE was more effective than mild therapeutic hypothermia in recovering myocardial function and activation of the pro-survival kinases Akt and ERK after ECLS.

Improved Outcome of Cardiac Extracorporeal Membrane Oxygenation in Infants and Children Using Magnetic Levitation Centrifugal Pumps

Extracorporeal membrane oxygenation (ECMO) has traditionally been and, for the most part, still is being performed using roller pumps. Use of first-generation centrifugal pumps has yielded controversial outcomes, perhaps due to mechanical properties of the same and the ensuing risk of hemolysis and renal morbidity. Latest-generation centrifugal pumps, using magnetic levitation (ML), exhibit mechanical properties which may have overcome limitations of first-generation devices. This retrospective study aimed to assess the safety and efficacy of veno-arterial (V-A) ECMO for cardiac indications in neonates, infants, and children, using standard (SP) and latest-generation ML centrifugal pumps. Between 2002 and 2014, 33 consecutive neonates, infants, and young children were supported using V-A ECMO for cardiac indications. There were 21 males and 12 females, with median age of 29 days (4 days-5 years) and a median body weight of 3.2 kg (1.9-18 kg). Indication for V-A ECMO were acute circulatory collapse in ICU or ward after cardiac repair in 16 (49%) patients, failure to wean after repair of complex congenital heart disease in 9 (27%), fulminant myocarditis in 4 (12%), preoperative sepsis in 2 (6%), and refractory tachy-arrhythmias in 2 (6%). Central cannulation was used in 27 (81%) patients and peripheral in 6. Seven (21%) patients were supported with SP and 26 (79%) with ML centrifugal pumps. Median duration of support was 82 h (range 24-672 h), with 26 (79%) patients weaned from support. Three patients required a second ECMO run but died on support. Seventeen (51%) patients required peritoneal dialysis for acute renal failure. Overall survival to discharge was 39% (13/33 patients). All patients with fulminant myocarditis and with refractory arrhythmias were weaned, and five (83%) survived, whereas no patient supported for sepsis survived. Risk factors for hospital mortality included lower (<2.5 kg) body weight (P = 0.02) and rescue ECMO after cardiac repair (P = 0.03). During a median follow-up of 34 months (range 4-62 months), there were three (23%) late deaths and two late survivors with neurological sequelae. Weaning rate (5/7 vs. 21/26, P = NS) and prevalence of renal failure requiring dialysis (4/7 vs. 13/26, P = NS) were comparable between SP and ML ECMO groups. Patients supported with ML had a trend toward higher hospital survival (1/7 vs. 12/26, P = 0.07) and significantly higher late survival (0/7 vs. 10/26, P = 0.05). The present experience shows that V-A ECMO for cardiac indications using centrifugal pumps in infants and children yields outcomes absolutely comparable to international registry (ELSO) data using mostly roller pumps. Although changes in practice may have contributed to these results, use of ML centrifugal pumps appears to further improve end-organ recovery and hospital and late survival.

Pulsatile flow decreases gaseous micro-bubble filtering properties of oxygenators without integrated arterial filters during cardiopulmonary bypass

OBJECTIVES Cardiopulmonary bypass (CPB) has a risk of embolic injury with an important role of gaseous micro-bubbles (GMBs), coming from CPB-circuit. Pulsatile perfusion (PP) can provide specific conditions for supplementary GMB-activity with respect to non-pulsatile (NP). We aimed to test GMB-filtering properties of three modern oxygenators under pulsatile and non-pulsatile conditions. METHODS Seventy-eight patients undergoing on-pump myocardial revascularization were randomized prospectively into three equal groups according to the oxygenator model used during CPB. Terumo Capiox-FX25, Sorin Synthesis or Maquet Quadrox-i-Adult membrane oxygenators were tested. Each group was divided equally to undergo PP or NP. GMBs were counted by means of a GAMPT-BCC200 bubble-counter with two probes placed at preoxygenator and arterial post-filter positions. Results were evaluated in terms of GMB-volume, GMB-number, amount of large over-ranged GMBs, a series of filtering indices and major neurological outcomes. RESULTS PP decreased GMB-filtering properties of the tested oxygenators. Those with integrated filters (CAPIOX-FX25 and SYNTHESIS) did not show significant differences between perfusion groups, while QUADROX-i oxygenator with external arterial filter showed significantly higher GMB-volume (P < 0.001), GMB-number (P < 0.001) and amount of over-ranged bubbles (P < 0.001) detected in arterial line during PP. Despite the differences in filtering capacity of all circuits with both types of perfusion, no important differences in clinical outcomes and major neurological events were observed. CONCLUSIONS Pulsatile flow decreases gaseous micro-bubble filtering properties of oxygenators without integrated arterial filters during CPB. PP requires specially designed circuit components to avoid the risk of additional GMB delivery.

Clinical Evaluation of New Generation Oxygenators With Integrated Arterial Line Filters for Cardiopulmonary Bypass

New generation oxygenators with integrated arterial line filters have been marketed to improve the efficacy of cardiopulmonary bypass (CPB). Differences in designs, materials, coating surfaces, pore size of arterial filter, and static prime exist between the oxygenators. Despite abundant preclinical data, literature lacks clinical studies. From September 2010 to March 2011, 80 consecutive patients were randomized to CPB using Terumo Capiox FX25 (40 patients, Group-T) or Sorin Synthesis (40 patients, Group-S) oxygenators. Pressure drop and gas exchange efficacy were registered during CPB. High-sensitivity C-reactive protein (hs-CRP), white blood cells (WBCs), fluid balance, activated clotting time, international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen, platelets (PLTs), serum albumin, and total proteins were measured perioperatively at different timepoints. Clinical outcome was recorded. Repeated measure analysis of variance and nonparametric statistics assessed between-groups and during time differences. The two groups showed similar baseline and intraoperative variables. No differences were recorded in pressure drop and gas exchange (group-P and group*time-P = N.S. for all) during CPB. Despite similar fluid balance (P = N.S. for static/dynamic priming and ΔVolume administered intraoperatively), Group-T showed higher hs-CRP (group-P = 0.034), aPTT (group-P = 0.0001), and INR (group-P= 0.05), with lower serum albumin (group-P = 0.014), total proteins (group-P = 0.0001), fibrinogen (group-P = 0.041), and PLTs (group-P = 0.021). Group-T also showed higher postoperative bleeding (group-P = 0.009) and need for transfusions (P = 0.008 for packed red cells and P = 0.0001 for fresh frozen plasma and total transfused volumes). However, clinical outcome was comparable (P = N.S. for all clinical endpoints). Both oxygenators proved effective and resulted in comparable clinical outcomes. However, Sorin Synthesis seems to reduce inflammation and better preserve the coagulative cascade and serum proteins, resulting in lower transfusions and post-CPB inflammatory response.

Continuous Metabolic Monitoring in Infant Cardiac Surgery: Toward an Individualized Cardiopulmonary Bypass Strategy

Cardiopulmonary bypass (CPB) in infants is associated with morbidity due to systemic inflammatory response syndrome (SIRS). Strategies to mitigate SIRS include management of perfusion temperature, hemodilution, circuit miniaturization, and biocompatibility. Traditionally, perfusion parameters have been based on body weight. However, intraoperative monitoring of systemic and cerebral metabolic parameters suggest that often, nominal CPB flows may be overestimated. The aim of the study was to assess the safety and efficacy of continuous metabolic monitoring to manage CPB in infants during open-heart repair. Between December 2013 and October 2014, 31 consecutive neonates, infants, and young children undergoing surgery using normothermic CPB were enrolled. There were 18 male and 13 female infants, aged 1.4 ± 1.7 years, with a mean body weight of 7.8 ± 3.8 kg and body surface area of 0.39 m(2) . The study was divided into two phases: (i) safety assessment; the first 20 patients were managed according to conventional CPB flows (150 mL/min/kg), except for a 20-min test during which CPB was adjusted to the minimum flow to maintain MVO2>70% and rSO2>45% (group A); (ii) efficacy assessment; the following 11 patients were exclusively managed adjusting flows to maintain MVO2>70% and rSO2>45% for the entire duration of CPB (group B). Hemodynamic, metabolic, and clinical variables were compared within and between patient groups. Demographic variables were comparable in the two groups. In group A, the 20-min test allowed reduction of CPB flows greater than 10%, with no impact on pH, blood gas exchange, and lactate. In group B, metabolic monitoring resulted in no significant variation of endpoint parameters, when compared with group A patients (standard CPB), except for a 10% reduction of nominal flows. There was no mortality and no neurologic morbidity in either group. Morbidity was comparable in the two groups, including: inotropic and/or mechanical circulatory support (8 vs. 1, group A vs. B, P = 0.07), reexploration for bleeding (1 vs. none, P = not significant [NS]), renal failure requiring dialysis (none vs. 1, P = NS), prolonged ventilation (9 vs. 4, P = NS), and sepsis (2 vs. 1, P = NS). The present study shows that normothermic CPB in neonates, infants, and young children can be safely managed exclusively by systemic and cerebral metabolic monitoring. This strategy allows reduction of at least 10% of predicted CPB flows under normothermia and may lay the ground for further tailoring of CPB parameters to individual patient needs.

Oxygenator Is the Main Responsible for Leukocyte Activation in Experimental Model of Extracorporeal Circulation: A Cautionary Tale.

In order to assess mechanisms underlying inflammatory activation during extracorporeal circulation (ECC), several small animal models of ECC have been proposed recently. The majority of them are based on home-made, nonstandardized, and hardly reproducible oxygenators. The present study has generated fundamental information on the role of oxygenator of ECC in activating inflammatory signaling pathways on leukocytes, leading to systemic inflammatory response, and organ dysfunction. The present results suggest that experimental animal models of ECC used in translational research on inflammatory response should be based on standardized, reproducible oxygenators with clinical characteristics.