The Jena universal perfusion system: a universal cardiopulmonary bypass circuit for cardiac surgery
http://www.100md.com
《血管的通路杂志》
Department of Cardiothoracic Surgery, Friedrich Schiller University, Erlanger Allee 101, 07747 Jena, Germany
Abstract
Cardiopulmonary bypass (CPB) is a standard technique in cardiac surgery, which itself contributes to postoperative morbidity. Neurologic sequelae after CPB is caused by air embolism or systemic inflammatory response due to artificial surface and is closely related to the characteristics of the extracorporeal circuit. Minimized systems without a venous reservoir take these factors into account. They require a differentiated volume management to avoid excessive negative pressure in the venous line, which may lead to spontaneous formation of microbubbles and are said to cause air embolism. Perfusion technology also offers systems with closed soft-bag and open hard-shell reservoirs, that require individual setups with little flexibility. We developed an all-purpose perfusion system for application as cardiopulmonary bypass. The central part is a compound reservoir, consisting of a lower hard shell and an upper self-expanding shell, which is capable of actively increasing volume. It allows application of the circuit as closed or open system. Crossclamping the inflow turns the system into a minimized circuit, in which the reservoir compensates volume when backflow is low and safeguards against excessive subzero pressure. The system has been applied in pilot experiments. In cardiac surgery today patients present at higher ages and with complex comorbidities. Not all of them are suitable candidates for off-pump procedures and might profit from perfusion technology with reduced adverse effects. The Jena Universal Perfusion System (JUPS) may be applied as a minimized system with the option to compensate low venous backflow and allows flexible extension to a closed or open circuit anytime during the procedure.
Key Words: Cardiopulmonary bypass; Minimized extracorporeal circuit; Systemic inflammatory response
1. Background
Extracorporeal circulation is a standard techique in modern cardiac surgery. Introduced in 1953 by John Gibbon, cardiopulmonary bypass (CPB) today has become a routine clinical application. The principle of CPB has remained unchanged since its introduction, however, perfusion technology made tremendous progress to meet specific requirements and increase patient safety. Despite various advances, two issues associated with CPB remain a matter of debate and are closely related to components and characteristics of the extracorporeal circuit.
A major concern with regard to the application of cardiopulmonary bypass is the incidence of air embolism, which may be a cause of neurologic sequelae after CPB and contribute to postoperative morbidity. The macroscopic entry of air into the extracorporeal circuit is rare and mostly a consequence of leakage or faulty application. Several authors, however, have described the spontaneous formation of microbubbles in the extracorporeal circuit, which is associated with excessive negative pressures in particular in the venous part of the circuit [1]. As setup and components play a key role for pressure conditions and the automatic elimination of foreign air in the circuit, characteristics of the system may influence the incidence of adverse neurologic outcome.
The primary perfusion system for CPB today is the open system, which consists of an oxygenator and a hard-shell reservoir with fixed shape and volume for the collection of venous blood. Open systems are characterized by direct blood–air contact in the reservoir and passive drainage of venous return. Negative pressures up to –35 mmHg in the venous line and the right side of the heart are common. The reservoir automatically eliminates large amounts of air in the venous line, thus reducing the risk of air embolism. This characteristic along with the capability of open systems to compensate for insufficient venous return with volume from the reservoir has led to their wide clinical application.
A second issue of debate with regard to extracorporeal circulation is the activation of inflammatory pathways through cardiopulmonary bypass [2]. Inflammation triggered by CPB can lead to organ dysfunction and disarrangement of hemostaseologic and fibrinologic cascades [3,4]. Characteristics of the extracorporeal circuit play a key role in the degree of inflammatory activation, as the decisive factors are contact of blood to artificial surfaces and a direct blood–air interface. The role of blood–air contact in systemic inflammatory response (SIRS) is well known: several authors were able to show elevated markers of systemic inflammation during and after CPB in patients treated with an open reservoir in comparison to those with a closed venous reservoir [5,6]. Recognizing the importance of contact to artificial surfaces, a focus of research has been set on the development of minimized – or low-prime-systems. Apart from the apparent advantage of requiring less priming volume, several investigators were actually able to show, that surface reduction and the avoidance of a direct blood–air interface by removal of the venous reservoir is associated with less systemic inflammatory activation as a consequence to CPB [7–9]. Wippermann et al. were able to show less activation of hemostaseologic variables during and after application of minimized systems in comparison to standard cardiopulmonary bypass [10].
In the clinical setting, minimized systems are characterized by active drainage of venous return through suction applied by a rotary blood pump. This fact has been found to be disadvantageous under certain conditions: when backflow is low, excessive negative pressure up to –600 mmHg may result due to inertia of the pump and cause spontaneous formation of microbubbles in the venous line. Excessive subzero pressure may be passed on to the right atrium and through functionally silent shunts to the left side of the heart and eventually cause aspiration of air, e.g. through arteriotomy during CABG [1]. With the reservoir removed in minimized systems, the perfusionist may not compensate for insufficient venous return with additional volume. Thus, minimized systems require a particular differentiated volume management and bring up new challenges in the clinical application of cardiopulmonary bypass.
Currently a variety of systems with numerous modifications are available, focusing on different aspects of perfusion technology. Minimized, closed and open systems were developed for specific indications and require independent setups with little or no flexibility. Despite advances of perfusion technology, present systems are not ideal and offer the potential for improvement. With the intention to devise an all-purpose CPB circuit for flexible clinical application with any method of perfusion, we devised a universal perfusion system – the Jena Universal Perfusion System (JUPS).
2. Description of the JUPS
The system was developed as a universal cardiopulmonary bypass circuit for cardiac surgery. The central part is a new type of reservoir, which is an assembly of two components: the lower half is comparable to a standard hard-shell reservoir as applied in conventional CPB-systems today. The upper half is a foldable, self-expanding shell, which has extractive force and is capable of actively increasing its volume (Fig. 1). Volume and self-expanding force may be adjusted by flexible springs on the outside. The reservoir may be combined with equipment for cardiotomy suction to recirculate shed blood from the operating field. It is part of a circuit, which is comparable to the present CPB systems in clinical application today: venous blood enters the reservoir by passive drainage and is then actively forwarded by a rotary blood pump into the oxygenator. The pump automatically reduces flow when venous return is low.
Two additional components were integrated into the circuit. A tube bypassing the reservoir from the venous line to the centrifugal pump was introduced, which allows optional exclusion of the reservoir by crossclamping the inflow, thus running the system as a minimized circuit. Secondly, a one-way-valve was inserted between the outflow of the reservoir and the centrifugal pump, which directs flow toward the pump. The valve becomes particularly important when the circuit is applied as a minimized system: it then acts as a safeguard against excessive negative pressure by automatically opening when pressure in the venous segment of the circuit drops below –75 mmHg. Then with the reservoir filled with priming solution, negative pressure is compensated to counteract formation of microbubbles.
An air inlet on top of the reservoir may optionally be open to the atmosphere or closed, thus permitting application of the reservoir with or without a direct blood–air interface. When the air inlet on top of the reservoir is closed, its capability to self-expand accounts for vacuum assisted drainage of venous return (Fig. 2). The system permits shifting from closed CPB to standard open bypass at any time during the surgical procedure by opening the air-inlet (Fig. 3).
The JUPS may be applied with any method of perfusion in clinical application today. It allows shifting from a minimzed to a closed and open circuit at any time during the procedure without the requirement to replace components or the entire circuit. If an unexpected change in operation strategy occurs – e.g. an extension of the procedure from revascularization only to valve procedures, the circuit can flexibly be extended to a closed or open system – according to requirements and with the least invasive technique.
3. Evaluation of the JUPS in pilot experiments
The JUPS was applied as a prototype in two 30 kg pigs for primary evaluation. The intention of the pilot study was to confirm the function of a self-expanding reservoir in an experimental setting and conduct basic hemodynamic measurements.
Prior to CPB the circuit was primed with 0.75 l of regular saline solution. After cannulation with a 24 F arterial cannula and a 36 F two-stage venous cannula, minimized CPB was initiated with an average flow of 2.2–3.1 l/min. Pressures were monitored at the level of the right atrium. To determine the lowest subzero pressure generated by the rotary blood pump, the reservoir was excluded from the circuit and – after steady conditions – the venous line was crossclamped. Pressure in the venous line rapidly decreased to –210 mmHg. In a second run, the reservoir was allowed to compensate volume in the minimized circuit (setup as Fig. 1; Fig. 4). After sudden occlusion, pressure in the venous line did not drop below –75 mmHg.
During the experiment, the perfusion mode was changed from minimized to closed and open cardiopulmonary bypass. When the JUPS was applied as a closed circuit, venous drainage was vacuum assisted but pressure at the right atrial level did not exceed –55 mmHg in the prototype (setup as Fig. 2). When the system was applied as an open circuit, negative pressure in the venous line did not exceed –30 mmHg (setup as Fig. 3).
During the pilot experiment, the circuit was flexibly changed between perfusion methods without stopping cardiopulmonary bypass. Excessive subzero pressures as described in minimized systems were not observed in the prototype with the flexible reservoir part of the circuit.
4. Comment
During the past decade, demographic development has led to an increase of surgical procedures in patients at higher ages and with complex comorbidities. Advanced techniques in cardiac surgery such as off-pump or minimal invasive surgery offer treatment options for this growing population, however, not all of these patients are suitable candidates for interventional techniques or off-pump surgery.
As cardiopulmonary bypass itself is an invasive technique contributing to postoperative morbidity, such patients are likely to profit from perfusion technology, that decreases its deleterious effects by surface reduction and avoidance of air contact and still offers maximum safety by reserving options of a flexible and modifiable curcuit. With JUPS, cardiopulmonary bypass as a minimized circuit is possible without the risk of excessive negative pressure by ensuring volume compensation at any time. The opportunity to shift to a circuit with a closed reservoir or to a standard open system with a blood–air interface preserves maximum flexibility as long as circulatory support is required and presents an increase of patient safety. If necessary, JUPS permits continuous circulatory support from the emergency room through the surgical procedure, and postoperatively in the intensive care unit, without the requirement to change the circuit. The system may contribute to making cardiopulmonary bypass a more predictable procedure for the patient by:
its application as a minimized system with reduced surface and priming volume
the option to compensate volume and avoid excessive negative pressure in a minimized system configuration
flexibly changing to a closed or open circuit without the requirement to stop cardiopulmonary bypass
The system has been applied as a prototype in an experimental setup, however, systematic studies for detailed evaluation are in progress. The system has been patented nationally, with international patents pending [11,12].
Acknowledgements
The authors would like to express their thanks to Dr Anas Aboud, to Mirko Kaluza and to Dr Parwis Rahmanian for their assistance in the experimental setup and their contribution to the manuscript. We would also like to thank Jens Geiling for his excellent contributions in artwork.
References
Liebing K, Kaluza M, Wippermann J, Stock U, Wahlers T. Linksventrikulaere Luftaspirationsgefahr bei Perfusionssystemen mit direkter venoeser Drainage durch die arterielle Blutpumpe. Kardiotechnik 2004; 1:9–10.
Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993; 55:552–559.
Asimakopoulous G. Mechanisms of the systemic inflammatory response. Perfusion 1999; 14:269–277.
Bracey AW, Radowancevic R. The hematologic effects of cardiopulonary bypass and the use of hemotherapy in coronary artery bypass crafting. Arch Pathol Lab Med 1993; 118:411–416.
Schnberger JP, Everts PA, Hoffmann J. Systemic blood activation with open and closed venous reservoir. Ann Thorac Surg 1995; 59:1549–1555.
Brown Mahoney C, Donelly JE. Impact of closed versus open venous reservoirs on patient outcome in isolated coronary bypass surgery. Perfusion 2000; 15:467–472.
McCusker K, Vijay V, DeBois W, Helm R, Sisto D. MAST sytem: a new condensed cardiopulmonary bypass circuit for adult cardiac surgery. Perfusion 2001; 16:447–452.
DeBois W, Sukhran Y, McVey J. Reduction in homologous blood transfusion using a low prime circuit. J Ex-Corporeal Technol 1996; 28:58–62.
Shapira OM, Aldea GS, Treanor PR, Chartrand RM, DeAndrade KM, Lazar HL, Shemin RJ. Reduction of allogeneic blood transfusions after open heart surgery operations by lowering cardiopulmonary bypass prime volume. Ann Thorac Surg 1998; 65:724–730.
Wippermann J, Albes J, Hartrumpf M, Kaluza M, Vollandt R, Bruhin R, Wahlers T. Comparison of minimally invasive closed circuit extracorporeal circulation with conventional cardiopulmonary bypass and with off-pump technique in CABG-patients: selected parameters of anticoagulation and inflammatory systems. Eur J Cardiothorac Surg Jul 2005; 28:127–132.
Liebing K Erfinder Patentdokument DE. 103 53 418 A1 2005.06.23Anmelder: Friedrich Schiller University Jena.
Liebing K, Wahlers T, Kaluza M Erfinder Patentanmeldung Nr. 10 2005 029 682.33Anmelder: Friedrich Schiller University Jena.(Alexander Lauten, Kai Liebing, Ulrich Fr)
Abstract
Cardiopulmonary bypass (CPB) is a standard technique in cardiac surgery, which itself contributes to postoperative morbidity. Neurologic sequelae after CPB is caused by air embolism or systemic inflammatory response due to artificial surface and is closely related to the characteristics of the extracorporeal circuit. Minimized systems without a venous reservoir take these factors into account. They require a differentiated volume management to avoid excessive negative pressure in the venous line, which may lead to spontaneous formation of microbubbles and are said to cause air embolism. Perfusion technology also offers systems with closed soft-bag and open hard-shell reservoirs, that require individual setups with little flexibility. We developed an all-purpose perfusion system for application as cardiopulmonary bypass. The central part is a compound reservoir, consisting of a lower hard shell and an upper self-expanding shell, which is capable of actively increasing volume. It allows application of the circuit as closed or open system. Crossclamping the inflow turns the system into a minimized circuit, in which the reservoir compensates volume when backflow is low and safeguards against excessive subzero pressure. The system has been applied in pilot experiments. In cardiac surgery today patients present at higher ages and with complex comorbidities. Not all of them are suitable candidates for off-pump procedures and might profit from perfusion technology with reduced adverse effects. The Jena Universal Perfusion System (JUPS) may be applied as a minimized system with the option to compensate low venous backflow and allows flexible extension to a closed or open circuit anytime during the procedure.
Key Words: Cardiopulmonary bypass; Minimized extracorporeal circuit; Systemic inflammatory response
1. Background
Extracorporeal circulation is a standard techique in modern cardiac surgery. Introduced in 1953 by John Gibbon, cardiopulmonary bypass (CPB) today has become a routine clinical application. The principle of CPB has remained unchanged since its introduction, however, perfusion technology made tremendous progress to meet specific requirements and increase patient safety. Despite various advances, two issues associated with CPB remain a matter of debate and are closely related to components and characteristics of the extracorporeal circuit.
A major concern with regard to the application of cardiopulmonary bypass is the incidence of air embolism, which may be a cause of neurologic sequelae after CPB and contribute to postoperative morbidity. The macroscopic entry of air into the extracorporeal circuit is rare and mostly a consequence of leakage or faulty application. Several authors, however, have described the spontaneous formation of microbubbles in the extracorporeal circuit, which is associated with excessive negative pressures in particular in the venous part of the circuit [1]. As setup and components play a key role for pressure conditions and the automatic elimination of foreign air in the circuit, characteristics of the system may influence the incidence of adverse neurologic outcome.
The primary perfusion system for CPB today is the open system, which consists of an oxygenator and a hard-shell reservoir with fixed shape and volume for the collection of venous blood. Open systems are characterized by direct blood–air contact in the reservoir and passive drainage of venous return. Negative pressures up to –35 mmHg in the venous line and the right side of the heart are common. The reservoir automatically eliminates large amounts of air in the venous line, thus reducing the risk of air embolism. This characteristic along with the capability of open systems to compensate for insufficient venous return with volume from the reservoir has led to their wide clinical application.
A second issue of debate with regard to extracorporeal circulation is the activation of inflammatory pathways through cardiopulmonary bypass [2]. Inflammation triggered by CPB can lead to organ dysfunction and disarrangement of hemostaseologic and fibrinologic cascades [3,4]. Characteristics of the extracorporeal circuit play a key role in the degree of inflammatory activation, as the decisive factors are contact of blood to artificial surfaces and a direct blood–air interface. The role of blood–air contact in systemic inflammatory response (SIRS) is well known: several authors were able to show elevated markers of systemic inflammation during and after CPB in patients treated with an open reservoir in comparison to those with a closed venous reservoir [5,6]. Recognizing the importance of contact to artificial surfaces, a focus of research has been set on the development of minimized – or low-prime-systems. Apart from the apparent advantage of requiring less priming volume, several investigators were actually able to show, that surface reduction and the avoidance of a direct blood–air interface by removal of the venous reservoir is associated with less systemic inflammatory activation as a consequence to CPB [7–9]. Wippermann et al. were able to show less activation of hemostaseologic variables during and after application of minimized systems in comparison to standard cardiopulmonary bypass [10].
In the clinical setting, minimized systems are characterized by active drainage of venous return through suction applied by a rotary blood pump. This fact has been found to be disadvantageous under certain conditions: when backflow is low, excessive negative pressure up to –600 mmHg may result due to inertia of the pump and cause spontaneous formation of microbubbles in the venous line. Excessive subzero pressure may be passed on to the right atrium and through functionally silent shunts to the left side of the heart and eventually cause aspiration of air, e.g. through arteriotomy during CABG [1]. With the reservoir removed in minimized systems, the perfusionist may not compensate for insufficient venous return with additional volume. Thus, minimized systems require a particular differentiated volume management and bring up new challenges in the clinical application of cardiopulmonary bypass.
Currently a variety of systems with numerous modifications are available, focusing on different aspects of perfusion technology. Minimized, closed and open systems were developed for specific indications and require independent setups with little or no flexibility. Despite advances of perfusion technology, present systems are not ideal and offer the potential for improvement. With the intention to devise an all-purpose CPB circuit for flexible clinical application with any method of perfusion, we devised a universal perfusion system – the Jena Universal Perfusion System (JUPS).
2. Description of the JUPS
The system was developed as a universal cardiopulmonary bypass circuit for cardiac surgery. The central part is a new type of reservoir, which is an assembly of two components: the lower half is comparable to a standard hard-shell reservoir as applied in conventional CPB-systems today. The upper half is a foldable, self-expanding shell, which has extractive force and is capable of actively increasing its volume (Fig. 1). Volume and self-expanding force may be adjusted by flexible springs on the outside. The reservoir may be combined with equipment for cardiotomy suction to recirculate shed blood from the operating field. It is part of a circuit, which is comparable to the present CPB systems in clinical application today: venous blood enters the reservoir by passive drainage and is then actively forwarded by a rotary blood pump into the oxygenator. The pump automatically reduces flow when venous return is low.
Two additional components were integrated into the circuit. A tube bypassing the reservoir from the venous line to the centrifugal pump was introduced, which allows optional exclusion of the reservoir by crossclamping the inflow, thus running the system as a minimized circuit. Secondly, a one-way-valve was inserted between the outflow of the reservoir and the centrifugal pump, which directs flow toward the pump. The valve becomes particularly important when the circuit is applied as a minimized system: it then acts as a safeguard against excessive negative pressure by automatically opening when pressure in the venous segment of the circuit drops below –75 mmHg. Then with the reservoir filled with priming solution, negative pressure is compensated to counteract formation of microbubbles.
An air inlet on top of the reservoir may optionally be open to the atmosphere or closed, thus permitting application of the reservoir with or without a direct blood–air interface. When the air inlet on top of the reservoir is closed, its capability to self-expand accounts for vacuum assisted drainage of venous return (Fig. 2). The system permits shifting from closed CPB to standard open bypass at any time during the surgical procedure by opening the air-inlet (Fig. 3).
The JUPS may be applied with any method of perfusion in clinical application today. It allows shifting from a minimzed to a closed and open circuit at any time during the procedure without the requirement to replace components or the entire circuit. If an unexpected change in operation strategy occurs – e.g. an extension of the procedure from revascularization only to valve procedures, the circuit can flexibly be extended to a closed or open system – according to requirements and with the least invasive technique.
3. Evaluation of the JUPS in pilot experiments
The JUPS was applied as a prototype in two 30 kg pigs for primary evaluation. The intention of the pilot study was to confirm the function of a self-expanding reservoir in an experimental setting and conduct basic hemodynamic measurements.
Prior to CPB the circuit was primed with 0.75 l of regular saline solution. After cannulation with a 24 F arterial cannula and a 36 F two-stage venous cannula, minimized CPB was initiated with an average flow of 2.2–3.1 l/min. Pressures were monitored at the level of the right atrium. To determine the lowest subzero pressure generated by the rotary blood pump, the reservoir was excluded from the circuit and – after steady conditions – the venous line was crossclamped. Pressure in the venous line rapidly decreased to –210 mmHg. In a second run, the reservoir was allowed to compensate volume in the minimized circuit (setup as Fig. 1; Fig. 4). After sudden occlusion, pressure in the venous line did not drop below –75 mmHg.
During the experiment, the perfusion mode was changed from minimized to closed and open cardiopulmonary bypass. When the JUPS was applied as a closed circuit, venous drainage was vacuum assisted but pressure at the right atrial level did not exceed –55 mmHg in the prototype (setup as Fig. 2). When the system was applied as an open circuit, negative pressure in the venous line did not exceed –30 mmHg (setup as Fig. 3).
During the pilot experiment, the circuit was flexibly changed between perfusion methods without stopping cardiopulmonary bypass. Excessive subzero pressures as described in minimized systems were not observed in the prototype with the flexible reservoir part of the circuit.
4. Comment
During the past decade, demographic development has led to an increase of surgical procedures in patients at higher ages and with complex comorbidities. Advanced techniques in cardiac surgery such as off-pump or minimal invasive surgery offer treatment options for this growing population, however, not all of these patients are suitable candidates for interventional techniques or off-pump surgery.
As cardiopulmonary bypass itself is an invasive technique contributing to postoperative morbidity, such patients are likely to profit from perfusion technology, that decreases its deleterious effects by surface reduction and avoidance of air contact and still offers maximum safety by reserving options of a flexible and modifiable curcuit. With JUPS, cardiopulmonary bypass as a minimized circuit is possible without the risk of excessive negative pressure by ensuring volume compensation at any time. The opportunity to shift to a circuit with a closed reservoir or to a standard open system with a blood–air interface preserves maximum flexibility as long as circulatory support is required and presents an increase of patient safety. If necessary, JUPS permits continuous circulatory support from the emergency room through the surgical procedure, and postoperatively in the intensive care unit, without the requirement to change the circuit. The system may contribute to making cardiopulmonary bypass a more predictable procedure for the patient by:
its application as a minimized system with reduced surface and priming volume
the option to compensate volume and avoid excessive negative pressure in a minimized system configuration
flexibly changing to a closed or open circuit without the requirement to stop cardiopulmonary bypass
The system has been applied as a prototype in an experimental setup, however, systematic studies for detailed evaluation are in progress. The system has been patented nationally, with international patents pending [11,12].
Acknowledgements
The authors would like to express their thanks to Dr Anas Aboud, to Mirko Kaluza and to Dr Parwis Rahmanian for their assistance in the experimental setup and their contribution to the manuscript. We would also like to thank Jens Geiling for his excellent contributions in artwork.
References
Liebing K, Kaluza M, Wippermann J, Stock U, Wahlers T. Linksventrikulaere Luftaspirationsgefahr bei Perfusionssystemen mit direkter venoeser Drainage durch die arterielle Blutpumpe. Kardiotechnik 2004; 1:9–10.
Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 1993; 55:552–559.
Asimakopoulous G. Mechanisms of the systemic inflammatory response. Perfusion 1999; 14:269–277.
Bracey AW, Radowancevic R. The hematologic effects of cardiopulonary bypass and the use of hemotherapy in coronary artery bypass crafting. Arch Pathol Lab Med 1993; 118:411–416.
Schnberger JP, Everts PA, Hoffmann J. Systemic blood activation with open and closed venous reservoir. Ann Thorac Surg 1995; 59:1549–1555.
Brown Mahoney C, Donelly JE. Impact of closed versus open venous reservoirs on patient outcome in isolated coronary bypass surgery. Perfusion 2000; 15:467–472.
McCusker K, Vijay V, DeBois W, Helm R, Sisto D. MAST sytem: a new condensed cardiopulmonary bypass circuit for adult cardiac surgery. Perfusion 2001; 16:447–452.
DeBois W, Sukhran Y, McVey J. Reduction in homologous blood transfusion using a low prime circuit. J Ex-Corporeal Technol 1996; 28:58–62.
Shapira OM, Aldea GS, Treanor PR, Chartrand RM, DeAndrade KM, Lazar HL, Shemin RJ. Reduction of allogeneic blood transfusions after open heart surgery operations by lowering cardiopulmonary bypass prime volume. Ann Thorac Surg 1998; 65:724–730.
Wippermann J, Albes J, Hartrumpf M, Kaluza M, Vollandt R, Bruhin R, Wahlers T. Comparison of minimally invasive closed circuit extracorporeal circulation with conventional cardiopulmonary bypass and with off-pump technique in CABG-patients: selected parameters of anticoagulation and inflammatory systems. Eur J Cardiothorac Surg Jul 2005; 28:127–132.
Liebing K Erfinder Patentdokument DE. 103 53 418 A1 2005.06.23Anmelder: Friedrich Schiller University Jena.
Liebing K, Wahlers T, Kaluza M Erfinder Patentanmeldung Nr. 10 2005 029 682.33Anmelder: Friedrich Schiller University Jena.(Alexander Lauten, Kai Liebing, Ulrich Fr)