Blood conservation protocol based on modified ultrafiltration towards bloodless pediatric surgery

Fluid management and blood conservation should be the fi rst priority in perfusion fi eld interests to overcome in pediatric open-heart surgery. Cardiopulmonary Bypass (CPB) may cause severe hemodilution and an acute systemic infl ammatory response syndrome; hemodilution can leads to a dilutional coagulopathy with reduced levels of most hemostatic elements causing bleeding disorders and excessive perioperative blood loss. As systemic infl ammation response, the development of capillary fl uid leakage, causing protein and fl uids shift into interstitial space increasing total body water resulted in hypovolemia with the need for blood product transfusion [13] and increasing of the postoperative myocardial dysfunction and respiratory failure [4-6]. In the other side, there were accumulating evidence of the negative impact associated with Red Blood Cells (RBCs) transfusion on morbidity and mortality in the pediatric cardiac population, including infection risk, post-injury multiorgan failure, increased hospital and intensive care length of stay, and the costs [710]. The bloodless surgery is not a new concept in pediatric surgery but in fact, is a preferable choice; it will probably become the rule rather than the exception in the future. More effort has been put into reducing the use of blood components in pediatric cardiac surgical centers, however, homologous blood components transfusion continues to be used frequently [9,11]. Despite recent advances in CPB technology worldwide, the majority of neonates and infants in our country still require perioperative transfusion of homologous blood components. This study attempted to reduce the use of homologous blood components by a protocol strategy focused on; 1) Minimization of CPB circuit [1]. 2) Restrict the RBCs transfusion for <7 and Abstract


Introduction
Fluid management and blood conservation should be the fi rst priority in perfusion fi eld interests to overcome in pediatric open-heart surgery. Cardiopulmonary Bypass (CPB) may cause severe hemodilution and an acute systemic infl ammatory response syndrome; hemodilution can leads to a dilutional coagulopathy with reduced levels of most hemostatic elements causing bleeding disorders and excessive perioperative blood loss. As systemic infl ammation response, the development of capillary fl uid leakage, causing protein and fl uids shift into interstitial space increasing total body water resulted in hypovolemia with the need for blood product transfusion [1][2][3] and increasing of the postoperative myocardial dysfunction and respiratory failure [4][5][6]. In the other side, there were accumulating evidence of the negative impact associated with Red Blood Cells (RBCs) transfusion on morbidity and mortality in the pediatric cardiac population, including infection risk, post-injury multiorgan failure, increased hospital and intensive care length of stay, and the costs [7][8][9][10]. The bloodless surgery is not a new concept in pediatric surgery but in fact, is a preferable choice; it will probably become the rule rather than the exception in the future. More effort has been put into reducing the use of blood components in pediatric cardiac surgical centers, however, homologous blood components transfusion continues to be used frequently [9,11]. Despite recent advances in CPB technology worldwide, the majority of neonates and infants in our country still require perioperative transfusion of homologous blood components. This study attempted to reduce the use of homologous blood components by a protocol strategy focused on; 1) Minimization of CPB circuit [1]. 2) Restrict the RBCs transfusion for <7 and https://www.peertechz.com/journals/archives-of-clinical-hypertension Citation: Saleh M (2020) Blood conservation protocol based on modifi ed ultrafi ltration towards bloodless pediatric surgery. Arch Clin Hypertens 6(1): 001-012. DOI: https://dx.doi.org/10.17352/ach.000023 <8gm/dL hemoglobin level during bypass and postoperative respectively. 3) Salvage of blood components from the CPB unit residual autologous whole blood [1], which commonly discarded or only partially salvaged. For that resone the MUF was modifi ed and facilitated by creating Cardioplegia Delivery/ Conventional Ultra-fi ltration/Modifi ed Ultra-fi ltration Multifunction Circuit (CD/CUF/MUF MFC) as a basic part of blood conservation strategy towards bloodless pediatric cardiac surgery [12]. The using of such MFC in congenital CPB fi eld, which had been implemented with a great effi cacy in perfusion practice of all conducted pediatric cardiac surgeries during 2010 to 2016, offered bloodless cardiac surgery for pediatrics ≥6kg weights with routine CPB equipment. The study will be evaluate retrospectively the effi cacy of MFC, quantifying its use to get the zero fl uids balance, and the ability to minimize the exposure to allogeneic transfusion while maximizing the use of autologous blood components. So the study designed to investigate the impact of blood conservation protocol on fl uids management and blood components conservation with the estimation of some clinical outcomes.

Ethics and population
The current study was performed according to the Helsinki Declaration and approved by the research institution of Aswan University and I followed the rules of Aswan university hospital institutional review board, which considered the informed consent for cardiac surgery for all cases that obtained from the pediatric relatives. 600 pediatric underwent an elective corrective congenital heart surgery for repair a variety of congenital heart defects using CPB procedure from January 2010 to September 2016 at Aswan university hospital cardiac center, Aswan, Egypt. For the purpose of the retrospective study, patients were assigned randomly and equally into studied groups (IS, IIS, and IIIS) and control groups (IC, IIC, and IIIC) and classifi ed on weights base (30kg≥ groups IS and IC >20kg≥ groups IIS and IIC >10kg≥ groups IIIS and IIIC ≥3kg). The studied groups were obeyed the blood conservation protocol under discussion and the routine CPB procedures had been conducted to the control groups.

Demographic analysis and CPB data
The patients' demographics and perioperative characteristics were represented in Table 1, without statistically discernible differences between all groups. There were no postoperative complications, adverse neurologic events, and all patients survived.

The strategy of minimizing blood components transfusion
Protocol strategy was formulated then agreed by all operating teams, andit contains two branches; First: achieve hemodilution reduction and blood component conservation allowing all blood output of cardioplegia blood head to inter the cardioplegia heat exchanger ( Figure 5). Shortly, before the end of bypass the hemoconcentrator outlet is switched to the inlet of the cardioplegia heat exchanger and be disconnected from hemoconcentrator inlet by placing a clamp and start washing the CDS contents through its recirculation line slowly into the reservoir using the cardioplegia blood head, so it will be ready for MUF process. At the conclusion of the CPB and with the patients hemodynamics stability, arteriovenous MUF was performed for 20 min (instead of 10 min or less of routine MUF time of control groups) using MFC as following; the cardioplegia delivery line should be connected to one of the right atrium cannulae using the proper perfusion adaptor, once the target blood fl ow "7-10% of the calculated patient blood full fl ow" was reached, the fi ltrate line will be opened and fi ltration started with 150 and 200 mmHg hemoconcentrator Transmembrane Pressure (TMP) for groups IS, IIS and IIIS Prime components volumes (mL): Additional solutions and blood components Solutions: Homologous blood components volumes (mL): Calculated autologous blood components autotransfused: Clinical outcome characteristics      that, it remains as it is connected without changing the status of any of its components, neither during nor after MUF. Such safe and easy go back to bypass for the purpose of emergencies and deliver cardioplegia through CDS if needed.

Investigated parameters
Fluid management: Measuring CPB unit and MFC volumes, plasma water fi ltration rate per 2min during MUF, with performance and timing of zero crystalloids and colloids balance achievement. Blood components conservation: Calculating the homologous blood components transfusion since the time of operating room arrival until the end of fi rst day ICU including the blood products added to the prime. Measuring Hb level, total plasma protein concentration and platelets count values, so the autotransfused blood components amounts using MFC can be calculated. Clinical outcome characteristics: Investigate the conservation protocol impact on systolic pressure during MUF, inotropes doses, lactate level during operation, perioperative blood loss; the intraoperative blood loss was represented as the sum of blood calculated from swabs, discarded suction volumes and the chest drains' output, and postoperative blood loss was represented as the total volume of chest tubes during the fi rst day ICU stay, and fi nally postoperative durations of intubation, ICU and hospital stay.

Data statistical analysis
The studied population continuous data are presented as the mean ± standard deviation of the mean and two tailed Student's t-Test to examine signifi cant differences in measured parameters and collected data, using statistical package IBM SPSS.

Results
Results showed successful implementation of blood conservation protocol based on MFC. There was an achievement of zero crystalloids balance for all studied patients and zero colloids balance for most of them, decreasing the blood components transfusion and improve hemodynamic, coagulation and other organs functions resulted in postoperative morbidity reduction. Fluid management: Because 44 patients of group IIIS with weights range of 10-6kg experienced nonhemic prime, so in the purpose of the further data analysis, each of IIIS and IIIC groups was divided based on weights into two goups as following; 10 kg≥ groups IIISA and IIICA ≥6kg>groups IIISB and IIICB ≥3kg. As represented in Table 2 (Table 2).

Needs for transfusions have been decreased in patients
undergoing open heart surgery with the development of CPB management and transfusion reduction strategies. CPB in pediatric cardiac surgery exposes children to severe    hypothermia, hemodilution, and increase the blood vessels permeability because of the infl ammatory reaction due to surface contact activation, which leads to unfavorable alterations such as hemodynamics changes [13][14][15][16]. Total body water increases as a result of capillary permeability which often leads to tissue edema, followed by multiple organ dysfunctions principally in lungs, heart, and brain [17,18]. As an alternative to hemodilution, the potential negative impacts of blood transfusion have been discussed Signifi cantly [19], and its limited effi cacy with the high costs suppress every institution board to adopt the transfusion protocol to their own local situation and its ways to reduces blood transfusion. The improvements in blood conservation protocols will further capitalize our understanding of blood conservation benefi ts in pediatric cardiac surgery [20].
In the fi eld of bloodless CPB procedures; Vincent F and his colleagues recorded bloodless surgery in 9% of 0-6kg weight group with 185mL prime volume, which includes cardioplegia and ultrafi lter, and so 45%, 58% and 78% of 6-15kg, 15-20kg and 20-40kg weight groups respectively [21]. Transfusion-free CPB procedure for three cases weights 4.5, 3.5 and 3.1kg with the small circuit of 200mL prim volume have been reported using a dedicated pediatric heart-lung machine console with remote pump heads and intensive blood conservation efforts allowed the operation without the use of donor blood [22]. In a case report, stringent improvement of blood management strategies, particularly the downsizing of the cardiopulmonary bypass system, had enabled a transfusion-free arterial switch operation in a 1.7kg prematurely born neonate [23]. Obviously, pediatric bloodless CPB procedures were remarkably accomplished using mast mounted pumps, which is unfortunately unavailable in most developing countries.
The two motives of the current study were the patient's benefi ts and cost reduction without extra devices, where some techniques may reduce blood transfusion of an individual patient without cost reduction. In the early development stage of such protocol as a bloodless technique for pediatric CPB procedure to overcome rare blood groups and/or a blood units unavailability, we found such technique makes our center able to perform those cases, solving perfusion side problem of hemic prime, features of low morbidity and mortality have been experienced among those pediatrics, that motivated us to represent this technique in an executable, generally treated blood conservation protocol.
The fl uid management during congenital surgery should be in the midline between the two extremes poles; hemodilution pole and the blood components transfusion pole, in the matter of practical perfusion fi eld, fl uids management should be biased for one pole of them. The current blood conservation protocol biased to the hemodilution pole to the extreme level we can go and choice it as 21% Hct [24]. So we found the solution is using a limited non-hemic prime volume, and restrict the RBCs transfusion to the minimal quantities. The current protocol fulfi lled using our routine roller pumps is not easily accomplished, especially when applying to neonates of ≤10kg weights. In agreement with the importance of prime reduction [20], the routine prime of 700mL has been reduced to the range of 550-350mL for the studied groups. This reduction was mainly obtained by introduction of a new setting for the CPB components and miniaturization of a whole CPB unit, with creating MFC merge the three jobs in United reduced tubes in order to minimize the effect of dead volume of MUF routine circuit, also managing the heart-lung machine position relative to the surgical table was a signifi cant and maybe contributed to overall unit prime volume reduction more than the miniaturization of CPB unit itself. studies confi rming, the MUF considerably decreased the necessity for postoperative blood components transfusion [12,28,29], group IIISB showed signifi cant lower RBCs quantities as additional homologous blood components quantities in OR and the fi rst day ICU. There was a rational relation between zero fl uids balance achievement "especially colloids" and the reduction of homologous RBCs transfusion, where groups IS, IIS and IIISA did not receive any amounts of homologous blood components intraoperative and 24hours postoperative. As demonstrated in Figure 8, the current protocol shifted the Hb levels decrease from pre-bypass occurred in control groups to during bypass for studied groups, which was well tolerated by the hypothermia, where the main rationale for body cooling is to reduce metabolic rate suffi ciently providing end-organ protection to allow greater matching between oxygen consumption and delivery [30][31][32][33], that shifting facilitated by anesthesia team members' implementation of hemodilution restriction prior to CPB as a part of conservation protocol, which was a great help in to go with the blood transfusion to the minimal transfusion trigger (<7gm/dL) during bypass [34][35][36][37][38]. Then post MUF these levels showed insignifi cant values compared with their preoperative values except for group IIISB it didn't show such elevation, it was in the reason of incomplete MUF time to achieve the 100% colloids zero balance performance (Figure 7). The total protein concentration values showed the same pattern of hemoglobin levels as a part of blood components preserved under effect of the studied protocol ( Figure 9). Platelets count recovered at 24hours postoperatively and become insignifi cant lower compared with their pre-bypass count values ( Figure 10). By contrast to the commonly residual blood is to discarded the CPB unit residual blood or partially salvages it, because of dysfunctional platelets and subsequently impaired overall coagulation status point of view, and by agreeing to published data have shown that, most of the ill effects of CPB on platelets function and other coagulation factors are temporary and reversible within hours postoperatively [39], the conservation protocol under discussion ensures the competent preservation for patient's platelets. The large size platelets relative to the ultrafi lter membrane pores were concentrated during MUF process; farther more, the high concentration of MFC blood cells decrease the mobility of all platelets sizes, and so decrease the ability to be fi ltrated. In a comparison of current protocol with many techniques have been used to salvage the residual blood including centrifugation/washing, direct transfusion and ultrafi ltration during or post CPB, unfortunately some of them have adverse effects, as example cell saver will only save dysfunctional RBCs, because the using of high-speed centrifugal pump affects the rheological characteristics of erythrocytes interrupting its proper oxygenation role, also its limited availability which accepted to use in 12h after it was obtained, besides the cost of machine and consumables that raises the cost of regular pediatric cardiac surgery procedures. On the other hand for control groups, although the temporary effect of CPB on coagulation elements, we should avoid the temporarily destructive effect of signifi cant high prime volumes and blood components transfusions on the infl ammatory system in form of potentially trigger complement system activation pro-infl ammatory cytokines, neutrophil stimulation, and endothelial cell activation [40][41][42][43][44][45][46]. The successful bloodless procedures performed for groups IS, IIS and IIISA pediatrics, was confi rmed obviously with the signifi cant calculated amounts of RBCs, plasma, and total protein have been autotransfused for groups IS, IIS and IIISA compared with their control groups (Table 2). Although group IIISB showed signifi cant lesser hemic prime volume and signifi cant reduction of homologous blood components exposure in prime, intraoperative and 24hours postoperative compared with group IIICB, unfortunately, the protocol did not succeed to demonstrate bloodless procedure due to incomplete autotransfusion that represented in more "average 6 min" needed of MUF time in order to complete the achievement of 100% zero colloids balance (Figure 7). MUF using MFC provides more forcefully marked improvements in hemodynamic status immediately during MUF (Figure 11). In the fact of controlled hypothermic cardiac arrest may infl uence the trans-membrane fl uid exchange resulted in an increase of myocardial interstitial fl uid, many investigations have shown improvements in hemodynamics parameters after MUF including heart rate, left ventricular systolic function, systolic and diastolic blood pressure, right and left atrial pressures, pulmonary arterial pressure, cardiac function, and a reduction in myocardial wall thickness and myocardial edema [12,47,48], also the correlation of improving blood pressure with the increase of blood viscosity during MUF [49]. There was a decrease in systolic pressure accompanied by continues fi ltration for the last 4 minutes without replacement in order to chase MFC contents into the patient circulation as a fi nal replacement at the end of MUF process using ringer lactate solution added to the CPB unit, fortunately the former mentioned systolic pressure improvement during the fi rst 16minutes of MUF process makes the MFC contents chase process possible, by shifting up the systolic pressure falls into an acceptable systolic pressure range as shown in Figure 11. Consequently, the useful impact of the protocol on patient's circulation refl ects the cardiovascular performance improvements resulted in signifi cant reduction of dopamine dose for studied groups in the early postoperative period. Insignifi cant differences of lactate level values during operation for all groups demonstrated adequate vital organs oxygen delivery for the studied groups patients during bypass time and the successful rewarming technique used in this protocol, which include rewarming process time optimization and being shifted to the fi nal stage of CPB procedure, to be ended by the end of CPB procedure and immediately going to MUF, that ensures reduction of normothermic oxygen demand period which is unable to be compensated by the low Hg level during CPB. Using this technique, there was no effect on the spontaneous recovery of myocardium contractility at 28°C body temperature. May the reduction of pulmonary edema, limited blood components transfusion and the platelets count recovery of studied groups, resulted in such improvement in bleeding tendency outcome where prothrombin, factor VII, and fi brinogen levels elevated considerably by MUF which consistently been found to reduce bleeding [24], with better hemostasis clearly showed in shorter time of postoperative mechanical ventilation and ICU stay. There is an important safety feature for the usage of existing CDS such as; 1) Dedicated blood pumping for controlled CUF, that ensures the actual

Conclusion
There are sporadic successful reports of blood conservation surgery in pediatric cardiac surgery population without a concrete methodology or accepted guidelines to be adapted and implemented in the institutional practices. In most part, there are no accepted guidelines in what would be a safe Hct range during CPB in order to avoid cerebral and end-organ ischemic injuries. This observational study data demonstrated that; MFC as a basic part of the described conservation protocol was an effective and successful low-cost autotransfusion process, which facilitate the effi cient and safe reverse of hemodilution and offset the dilutional coagulopathy, that enabling to conducted bloodless CPB procedures for weights ≥6kg and minimal homologous blood components transfusion in weights <6kg using the routine CPB equipment. Since 2010 up to now, MFC has been practiced in the daily our institution practices as an ideal method to facilitate and improves fl uid balances perioperatively; get the benefi ts of reducing or eliminating transfusion without side effects or medical troubles and being associated with lesser inotropes support and attenuation of morbidity and postoperative durations.
Research frontiers: The current study helped to expand the safety and applicability of bloodless surgery using worldwide traditional CPB circuits, components, and roller pump machines. Further studies needed to cover the additional relevant requirements for example; the adjustment of acceptable hemodilution level during CPB, enhancement of patient preoperative Hct value, optimization of oxygen demand/supply monitoring during CPB and defi ne the risk on the biophysical properties of pressurized RBCs during MUF in groups IIISA and IIISB patients.

Acknowledgments
Many thanks, to the members of Aswan university hospital.