Minimal Invasive Extra-corporeal Circulation on End Stage Coronary Artery Disease Patients Undergoing Myocardial Revascularization

Background: Patients with coronary artery disease (CAD) undergoing myocardial revascularization, with concomitant heart failure dened by left ventricular ejection fraction (LVEF) lower than 35%, constitute a population at risk of poor long-term prognosis and limited survival. The benets of minimal invasive extracorporeal circulation (MiECC) on end stage coronary artery disease patients undergoing myocardial revascularization has not been described and evidenced by scientic studies. Materials and Methods: In this single-centre control study of 60 end stage coronary artery disease patients undergoing isolated coronary artery bypass grafting.The patients was divided in two contemporary groups: in group (MiECC), n= 30 coronary artery bypass grafting (CABG) was used MiECC, whereas, in group conventional extracorporeal circulation (cECC), n=30 CABG was used cECC. Results: Procedures of Group MiECC reported (mean values) of a DO 2i of 305 mL/min/m 2 in relation to O 2 ER i 21.5% vs a DO 2i of 288 mL/min/m 2 in relation to O 2 ER i 25.6% was found in group MiECC vs cECC (p=0.037). Lactate levels >3 mmol/L were reported in 7 group MiECC patients vs 20 group cECC patients (p=0.038), with blood glucose peak. Mean nadir Hb values during CPB were 9.7 g/dL in group MiECC vs 7.8 g/dL in group cECC (p = 0.044). CI during CPB was 2.4 L/min/m 2 in both groups. Total red blood cell administration was 8 units in group MiECC vs 21 units in group cECC (p=0.022). A glycemic peak was recorded in 7 patients of group MiECC vs 20 patients of group cECC (p=0.037). Conclusion:The MiECC technique on end stage coronary artery disease was associated with a higher DO 2i compared to cECC. MiECC patients showed a signicant reduction in red blood cells units administration, in peak intraoperative lactate levels, which correlated with better postoperative renal outcome and shorter length of stay.


Introduction
Patients with coronary artery disease (CAD) undergoing myocardial revascularization, with concomitant heart failure de ned by left ventricular ejection fraction (LVEF) lower than 35%, constitute a population at risk of poor long-term prognosis and limited survival [21]. Acute kidney injury (AKI) in this population frequently occur after cardiopulmonary bypass and the perioperative techniques and strategies selection could be crucial for the prevention.
The management and monitoring of metabolic parameters during extra-corporeal circulation has gained widespread adoption over the years, particularly in relation to the target values of oxygen delivery (DO 2 ) > 262 mL/min/m 2 , carbon dioxide production > 5.3, indexed oxygen extraction ratio (O 2 ER i ) < 25% [1][2][3], with average blood pressure values during cardiopulmonary bypass (CPB) of 50-70 mmHg. This has made it possible to reduce the incidence of postoperative acute kidney injury and to improve the management of aerobic vs anaerobic metabolism during cardiac surgery procedures. At the same time, minimally invasive extra-corporeal circulation (MiECC) technologies have been developed and introduced into clinical practice [4].
The aim of this study was to compare MiECC vs conventional extra-corporeal circulation (cECC) in end stage coronary artery disease patients undergoing myocardial revascularization, in terms of superiority in relation to metabolic parameters (maximum DO 2 , lower O 2 ER i ), red blood cell (RBC) consumption, duration of mechanical ventilation and peak postoperative serum creatinine.

Material And Methods
Population and study design Between February 2020 and May 2021, 60 patients aged > 75 to 83 years with a mean EuroSCORE II of 9.1-9.5% and left ventricular ejection fraction (LVEF) lower than 35% undergoing myocardial revascularization at our institution. A retrospective comparison was carried out in terms of maximum DO 2 and O 2 ER i < 25% for standard cardiac index value 2.4 (l/min/m 2 ). The patients was divided in two contemporary groups: in group "MiECC", n = 30 coronary artery bypass grafting (CABG) was used MiECC, whereas, in group "cECC", n = 30 CABG was used cECC (Table 1). Metabolic management through blood gas analysis integrated with the use of a metabolic parameter monitoring system during CPB was adopted in both groups. The study protocol was approved by the local ethics committee and all patients provided written informed consent to data treatment.

Data collection
Patients were selected according to the following criteria: Patients with coronary artery disease (CAD) undergoing myocardial revascularization, with concomitant heart failure and left ventricular ejection fraction (LVEF) lower than 35% and complete CPB and cardioplegic arrest had to be foreseen with an expected CPB duration > 90 min.
Patients were excluded if they presented abnormal plasma lactate levels (> 2 mmol/L) before entering CPB, liver failure, obesity, uncompensated diabetes, autoimmune disease, active infection, any immunosuppressive therapy, or coagulation disorder. Patients undergoing combined surgery (e.g. aortic valve replacement (AVR) + CABG, about 300 patients during the study period) or surgery with circulatory arrest or having preoperative hematocrit (Hct) < 27% were also excluded.
The cardiac surgery procedures that were analyzed for this study were CABG (n = 100). Preoperative data included patient demographics, baseline serum creatinine, left ventricular ejection fraction, comorbidities (chronic obstructive pulmonary disease, previous cerebrovascular accident), baseline hemoglobin (Hb), EuroSCORE II and New York Heart Association functional class [1].
Perioperative data included type of operation, CPB duration, nadir body temperature during CPB, nadir hematocrit (Hct) and Hb value (measured at the start of CPB and every 20 min thereafter), nadir DO 2i , nadir DO 2i /O 2 ER i ratio during CPB, nadir cardiac index (CI), nadir CI/mixed venous oxygen saturation (SvO 2 ), peak serum lactate and glucose during CPB and perioperative red blood cells administrations.
Postoperative data included peak serum creatinine, mechanical ventilation time and days spent in the intensive care unit (ICU).
The primary endpoints were: maximum DO 2i in relation to O 2 ER i during CPB compared between groups in terms of intraoperative lactate and glycemia trends. Secondary endpoints were: and total red blood cells consumption, peak postoperative serum creatinine level [5][6][7], mechanical ventilation time and length of ICU stay.

Anesthetics and surgical procedures
Patients were monitored with ve-lead electrocardiography, a left radial artery catheter, capnography, pulse oximetry, and rectal/urine bladder temperature sensors. Transesophageal echocardiography was performed in all patients. Anticoagulant therapy consisted of heparin sodium before CPB at 300 IU/kg to give an activated clotting time of > 480 s (ACT PLUS Medtronic, Minneapolis, MN, USA); for antagonization of heparin, 0.5-0.75 mg protamine was applied for every 100 heparin units. Anesthesia was induced with intravenous sufentanil (0.5-1 µg/kg) and midazolam (0.08-0.2 mg/kg), and tracheal intubation was facilitated with intravenous rocuronium (0.6-1 mg/kg). Anesthesia was maintained with propofol (2-5 mg/kg) and sufentanil (0.5-2.0 µg/kg), and the depth of anesthesia was monitored using bispectral index values (BIS XP, Aspect Medical System, Newton, MA, USA). The dosage of propofol was titrated to maintain bispectral index values between 40 and 60. AVR and CABG procedures were performed in median sternotomy with central cannulation, and surgical procedures were performed as routine by two surgeons. Concentrated red blood cells were transfused whenever Hb concentrations fell below 6 g/dL during surgery or below 8 g/dL during ICU stay. The goal of the hemoconcentration was to eliminate the excess of crystalloid administration.

Cardiopulmonary bypass setting
Group (MiECC) Closed circuit was performed with MiECC type III with Stöckert S5 heart-lung machine (LivaNova, London, UK) [4], whose design presents the characteristics of a volume management circuit (MiECTiS classi cation). A shunted venous soft-shell reservoir (Closed, Eurosets, Medolla, Italy) was used, the aortic root and pulmonary artery suction was managed in series venous return. Components (Biopassive Coating Phisio, LivaNova, London, UK) ( Fig. 1): venous-arterial line diameter (3/8), venous bubble-trap (Sherlock, Eurosets), a centrifugal pump (Biomedicus BPX80, Medtronic, Eden Prairie, MN, USA), and a polypropylene ber oxygenator (Alone, Eurosets). A bubble detection system was used to remove the air from the bubble trap and the circuit (Stockert, LivaNova). Circuit lling volume 500 mL crystalloid solution. 300 IU/kg of sodium heparin were administered, the activated clotting time prior to CPB was 501 s, the cannulas were connected to the air-free circuit, and the bypass with a closed system was set up, the reference value of management of venous drainage was the central venous pressure, maintained around 5 mmHg using urapidil as a vasodilator for higher values, or upon request of drainage by the surgeon, for lower values the Trendelenburg position was used [3,4,8,9]. All patients were treated with mild hypothermic CPB (34°C to 36°C). For the administration of myocardial protection, a closed circuit for cardioplegia with heat exchanger, with an infusion syringe pump in series and Saint Thomas solution with procaine were used and repeated every 30 min. The Landing monitoring system (Eurosets, Medolla, Italy) was used for DO 2 management during CPB. In both groups, blood gas analyses were performed using alpha-stat management with a blood gas analyzer (GEM Premier 3000 IQM, Instrumentation Laboratory, Werfen Group IVD company, Munchen, Germany) set to measure at 37°C [10]. On the basis of arterial blood data, we assessed the lowest Hct (percentage) on CPB; every 20 min, an arterial blood gas analysis, including blood glucose (mg/dL) and lactate (mmol/L) determination, was obtained. An Hb value < 6 g/dL during CPB was considered the trigger point for red blood cell transfusion. All patients received tranexamic acid according to routine protocol. Mean arterial pressure during CPB procedures was managed for values between 55-70 mmHg.

Group (cECC)
Open circuits with roller pumps (Admiral, Remo-well Eurosets, Medolla, Italy; Inspire 6 F, LivaNova, London, UK) were used for CPB. Pericardial blood was collected separately and could be processed or reinjected, if needed. The hard shell and softshell reservoir, oxygenating module and circuits were treated with phosphorylcholine (Agile Eurosets, Medolla, Italy; Phisio, LivaNova, London, UK). All patients were treated with mild hypothermic CPB (34°C to 36°C); a volume of 1250 mL crystalloid Ringer acetate solution was used for priming. The surgical procedures selected for this study do not justify the use of moderate hypothermia by falling below 34°C. For this reason, in the event of an initial increase in anaerobic metabolism, the rst compensation approach was not to lower the temperature but possibly liquids or red blood cells were integrated.
The hardware consisted of a Stöckert S5 heart-lung machine and a Stöckert Heater Cooler System 3T (LivaNova, London, UK) and the same cannulae were employed in both groups. For the administration of myocardial protection, a closed circuit for cardioplegia with heat exchanger, with an infusion syringe pump in series and Saint Thomas solution with procaine were used and repeated every 30 min. The Landing monitoring system (Eurosets, Medolla, Italy) was used for DO 2 management during CPB. In both groups, blood gas analyses were performed using alpha-stat management with a blood gas analyzer (GEM Premier 3000 IQM, Instrumentation Laboratory, Werfen Group IVD company, Munchen, Germany) set to measure at 37°C [10]. On the basis of arterial blood data, we assessed the lowest Hct (percentage) on CPB; every 20 min, an arterial blood gas analysis, including blood glucose (mg/dL) and lactate (mmol/L) determination, was obtained. An Hb value < 6 g/dL during CPB was considered the trigger point for red blood cell transfusion. All patients received tranexamic acid according to routine protocol. Mean arterial pressure during CPB procedures was managed for values between 55-70 mmHg. The management of mean arterial pressure the same in both groups.

Results
Demographic, preoperative and operative details of the patient population are shown in Tables 1 and 2. There are no difference between groups in terms on preoperative characteristics; the patients are isolated CABG procedures with LVEF low than 35% and assessed risk (Euroscore II 9.1-9.5% respectively).   values for the same consumption of blood products or hemodilution. In other words, mean DO 2 i was higher in MiECC group compared to the cECC with a higher Hg and Hct although with less transfusions since the ow rate of the two circuits would have been the same. The reduced heamodiluition with MiECC can also explain the better obtained results in this group in terms of lower indexed oxygen ratio. The link between hyperlactatemia and hyperglycemia through the above mechanism was con rmed by Revelly et al. in 2005 [11] in an elegant study dealing with cardiogenic or septic shock. The role of adrenergic agonists in this setting is well de ned: in cardiogenic shock, they are both endogenous or administered for cardiovascular therapy; in our model, they are endogenous in the majority of patients. None received epinephrine during CPB, and few received norepinephrine; however, unlike epinephrine, norepinephrine usually does not increase glucose production or induce an increase in plasma lactate concentration [12][13][14]. The two mechanisms leading to hyperlactatemia in various clinical conditions are therefore (i) anaerobic metabolism due to a poor DO 2 , and (ii) excess lactate production due to glucose failing to enter the oxidative pathway and being degraded to lactate by the glycolytic pathway [12,14,15]. These mechanisms, if independently considered, lead to different acid-base balance conditions, the former being accompanied by metabolic acidosis and the latter not necessarily so. However, in the clinical conditions of this observational study, the acid-base balance is constantly maintained at a normal pH value by bicarbonate corrections applied by the perfusionist whenever the base excess starts decreasing. Therefore, we are unable to identify differences in hyperlactatemia related to different values of peak blood lactate. However, the evidence that only four patients demonstrated hyperlactatemia without hyperglycemia and that only patients with an hyperlactatemia-HG hyperglycemia syndrome had a signi cantly lower value of DO 2 seems to con rm that, in our speci c clinical environment, hyperlactatemia and hyperglycemia are linked by the causative factor of a poor DO 2 , leading on one side to lactate production through the anaerobic pathway and on the other hand to a vicious cycle of lactate production due to the poor ability to use glucose through the aerobic pathway [2,5,10,16]. Reduced oxygen content in cases of acute anemia is usually compensated by reduced blood viscosity with increased blood ow in the microcirculation and by a compensatory increase in cardiac output [17]. This last mechanism may be impaired during CPB, where pump ow is usually adjusted on the basis of the patient's body surface area and temperature, not the Hb value. On the basis of our data, the main rationale for explaining hyperlactatemia during CPB is a DO 2 inadequate to guarantee the needed oxygen consumption of the patient.
In the present study, we investigated the role of potentially modi able factors related to CPB surgery in determining postoperative hyperlactatemia (e.g. due to inadequate perfusion) and HG hyperglycemia [18].  [19], who reported an hyperlactatemia incidence of 18%. Some of these factors were con rmed in our study, and other new factors were identi ed; however, our study population had a signi cantly shorter CPB duration and a lower degree of hemodilution during CPB. Given that both these factors seem to favor the onset of hyperlactatemia, the lower hyperlactatemia rate in our population is reasonably explained. The role of CPB duration in the determination of hyperlactatemia during CPB has been highlighted by other authors [1,19,20]. Moreover, the additional volume of crystalloid in the cECC group resulted in signi cant hemodilution as indicated by the mean hemoglobin values were more than 2 g/dL greater for the MiECC group during bypass. This factor alone could have had a large impact on the other dependent variables including lactate levels and oxygen delivery.

Study Limitations
Several study limitations should be acknowledged. First, we do not know the microcirculation response for the higher Hb values in the MiECC group compared to cECC. Second, the absence of in ammatory markers (cytokines) that could affect postoperative outcome; also on the indexed oxygen delivery. Third, eight pre-and intraoperative factors were found to be signi cantly associated with peak blood lactate level during CPB at univariate analysis: age, isolated coronary operation, lowest pump ow/blood pressure, requirement of vasopressor or inotropic medications, lowest temperature, Hct, and DO 2i were negatively correlated with peak blood lactate value during CPB, whereas CPB duration and peak blood glucose were positively correlated with peak blood lactate value during CPB. Despite this limitation, the samples were made homogeneous for the characteristics ( Table 1). The Landing monitoring system was used for DO 2 management during CPB; however, we don't record duration of time < 280ml/min/m 2 .
Finally, the choice to use one or the other was based on the availability of the perfusionists with and without skills needed to manage the MiECC technique is another limitation of the study.

Conclusion
The

Declarations
Ethics approval and consent to participate: The study was evaluated and approved by the institutional board for clinical trials, Anthea Hospital GVM Care&Research (internal protocol; decision 2020 Feb) and Informed consent was obtained from all subjects involved in the study.
Consent for publication: All authors have read and agreed to the published version of the manuscript.
Availability of data and materials: The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Figure 1
Minimal Invasive Extracorporeal Circulation (MiECC) during myocardial revascularization on end stage coronary artery disease patient.