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Gaseous microemboli reduction during cardiopulmonary bypass
Impact of extracorporeal circuit design
Stehouwer, M.C.
Publication date
2018
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Stehouwer, M. C. (2018). Gaseous microemboli reduction during cardiopulmonary bypass:
Impact of extracorporeal circuit design.
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voor het bijwonen van de openbare verdediging van het proefschrift
door
Marco Stehouwer
Woensdag 21 maart 2018 om 14:00 uur Agnietenkapel Oudezijds Voorburgwal 231 te Amsterdam Na aaoop bent u van harte uiuitgenodigd voor de receptie ter plaatse
In de avond is het
FEEST!!!
Vanaf 20:30 uur Fort Vechten, Reversezaal
Achterdijk 10-14 Bunnik www.fortvechten.nl
PParanimfen Guido Knegt
guidoknegt@yahoo.com
Arjen van Antwerpen
arjenvanantwerpen@gmail.com
voor het bijwonen van de openbare verdediging van het proefschrift
door
Marco Stehouwer
Woensdag 21 maart 2018 om 14:00 uur Agnietenkapel Oudezijds Voorburgwal 231 te Amsterdam Na aaoop bent u van harte uiuitgenodigd voor de receptie ter plaatse
In de avond is het
FEEST!!!
Vanaf 20:30 uur Fort Vechten, Reversezaal
Achterdijk 10-14 Bunnik www.fortvechten.nl
PParanimfen Guido Knegt
guidoknegt@yahoo.com
Arjen van Antwerpen
cardiopulmonary bypass:
2
Financial report was granted by: Heartbeat, Getinge Maquet Netherlands, LivaNova, Medtronic, GAMPT and Cardiac Care.
Cover design by Jan Bertels en ikke Printed by Gildeprint
ISBN: 978-94-6233-875-3
© Marco Stehouwer 2018. All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form, by any means without prior permission of the author. The copyright of articles that have been published has been transferred to the respective journals.
Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged
3
Gaseous microemboli reduction during
cardiopulmonary bypass:
Impact of extracorporeal circuit design.
ACADEMISCH PROEFSCHRIFT Ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam op gezag van Rector Magnificus
prof. dr. ir. K.I.J. Maex
ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op woensdag 21 maart 2018, te 14:00 uur door
Marinus Cornelis Stehouwer geboren te Papendrecht
4
PROMOTIECOMMISSIE:
Promotor: prof. mr. dr. B.A.J.M. de Mol AMC-UvA Copromotores: dr. R. de Vroege HagaZiekenhuis
dr. W. van Oeveren Rijksuniversiteit Groningen Overige leden: prof. dr. ir. C. Ince AMC-UvA
prof. dr. B. Preckel AMC-UvA
prof. dr. J.P.S. Henriques AMC-UvA prof. dr. F.M.J.J. De Somer Universiteit Gent prof. dr. A.M. Versluis Universiteit van Twente
dr. J. Kluin AMC-UvA
dr. B.P. van Putte St Antonius Ziekenhuis
5
CONTENTS
CHAPTER 1 Introduction 7 CHAPTER 2 Air removal efficiency of a venous bubble trap in a minimal extracorporeal circuit during coronary artery bypass grafting. 15 CHAPTER 3 Clinical evaluation of air removal characteristics of an oxygenator with integrated arterial filter in a minimal extracorporeal circuit. 31 CHAPTER 4 Clinical evaluation of the air handling properties of contemporary oxygenators with integrated arterial filter. 47 CHAPTER 5 Effect of oxygenator size on air removal characteristics: a clinical evaluation. 63 CHAPTER 6 In vitro air removal characteristics of two neonatal cardiopulmonary bypass systems: filtration may lead to fractionation of bubbles. 81 CHAPTER 7 Carbon dioxide flush of an integrated minimized perfusion circuit prior to priming prevents spontaneous air release into the arterial line during clinical use. 99 CHAPTER 8 Optical verification and in-vitro characterization of two commercially available acoustic bubble counters for cardiopulmonary bypass systems 117 CHAPTER 9 The influence of gaseous microemboli on biomarkers for inflammatory response, endothelial damage, oxidative stress, and neurological injury after minimized cardiopulmonary bypass 135 CHAPTER 10 DISCUSSION AND CONCLUSIONS 153 CHAPTER 11 Summary / Samenvatting 171 Summary 173 Samenvatting 179 Dankwoord 185 Curriculum vitae 1897
CHAPTER 1
Introduction
8
General introduction, aim and outline of the thesis
The potential role of gaseous microemboli in the adverse effects of cardiopulmonary bypass
Despite technical improvements in cardiopulmonary bypass (CPB) systems over the years, CPB is widely assumed to cause a wide variety of adverse effects with the ‘systemic inflammatory response’ playing the predominant role (1-3). Contact of blood with the artificial surface of the bypass circuit, ischaemia-reperfusion injury, endotoxaemia, and operative trauma are considered to be possible causes for this inflammatory reaction (4). Due to these effects, heart surgery using CPB is still perceived as a procedure that leads to excess morbidity and mortality (5). During CPB procedures, gaseous microemboli (GME) can originate from the extracorporeal circuit and can subsequently be released in the arterial bloodstream.
These GME are thought to contribute to the adverse outcomes of cardiac surgery (6). The blood-air surface of GME can activate the complement system and may cause protein denaturation. In addition, GME may damage the endothelium and obstruct the blood flow in the capillary vessels, causing transient ischaemia of end-organs (2). Consequently, GME could play a role in global oxidative stress, which is caused by ischaemia followed by reperfusion.
GME are considered to be iatrogenic events that are detectable in the arterial line, even during uneventful CPB. Actions required during CPB, such as blood sampling, transfusing volume or injecting drugs (7-9), lead to increased GME activity in the arterial line, which can be measured with ultrasound devices (10). Another possible cause of increased GME activity is the introduction of air into the venous line of the CPB circuit due to residual air in the venous cannula after connecting, the tubes or by the excessive negative pressure that can occur in closed loop systems (11-13). Besides the release of GME during uneventful CPB, accidental air introduction may also occur, although it is rare. A Dutch survey reported that at 23,500 CPB
procedures massive air embolism never reached the patient via the arterial line (14). Safety features such as level sensor and bubble sensors, found in contemporary heart-lung machines may prevent massive air passage. Also the role of modern CPB circuits cannot be ruled out. For instance, the hollow fiber oxygenators that are
9 currently used worldwide, can potentially evacuate massive air across the
microporous fibers (15).
Cardiopulmonary bypass design and air removal
In modern CPB, various CPB systems are used in the clinical setting on a day-to-day basis. To improve biocompatibility, various types of CPB systems have been
developed to minimize blood-air contact, foreign surface area and prime volume (16). It is important to realize that these CPB systems all have different air removal
characteristics.
In general, blood from the patient drains into a CPB system, successively comprising a venous reservoir, a blood pump, an oxygenator and an optional arterial filter. Venting and pericardial suction blood is collected in a cardiotomy reservoir and, after filtration through a sponge-like depth filter, re-enters the circulation. Based on type of venous reservoir, three types of CPB system can be differentiated.
The first and most commonly used circuit (probably >90%) is the so-called open system, which consists of a hard shell venous reservoir. In this reservoir, air is mainly scavenged by screen filtration and this can be considered as the first line of defence against air introduction.
The second system is the ‘semi-closed’ system and the venous reservoir in this system consists of a soft shell collapsible reservoir, which is a bag with an integrated mesh filter (approximately 100 µm pores).
The third system, a ‘closed loop’ system lacks a venous reservoir. Optionally, a venous filter may be used as a small safeguard against air introduction.
An important difference between the closed loop system and the other two systems is that the venous inflow and arterial outflow are not separated by a venous reservoir with dynamic blood volume properties. Because of this, the venous inflow and arterial outflow can only be equal. In the closed and semi-closed systems both flows are independent; the venous flow enters the system by gravity and the arterial flow is regulated with the arterial pump. In a closed loop system the arterial pump draws venous blood directly from the patient and this may compromise safety, since GME and incidental air can be transported more easily through these small systems (11,17,18). In contrast, two studies show that during CABG an open ECC circuit released the same amount of GME as the MECC closed loop system (19,20). These
10
contradictory results could be explained by the absence of the introduction of a blood-air mixture by venting, since the heart stays closed during CABG procedures. Two studies have shown the introduction of a blood-air mixture into the cardiotomy reservoir to be a source of GME, as measured in the arterial line (21,22). Potger et al (23) showed that this source of GME could be strongly reduced by separating the cardiotomy reservoir from the circulation. In this position, blood velocity is low and the bubbles can be scavenged by filtration and buoyancy properties, resulting in
improved air reduction. Since semi-closed CPB systems always have a separated cardiotomy reservoir, in contrast with open systems, this may explain that semi-closed circuits seem to have favourable air removal properties.
Aims of this thesis
This thesis will address six main questions about GME in cardiac surgery: 1. What is the effect of a venous filter on GME removal?
2. What is the influence of adding or removing an arterial filter? 3. What is the impact of oxygenator design on air removal?
4. How is air removal influenced by the design of the complete CPB circuit? 5. Do GME contribute to the adverse effects of CPB during cardiac surgery? 6. Is GME measurement using contemporary bubble counters reliable?
Outline of this thesis
This thesis addresses the air removal properties of entire CPB circuits, their designs and their specific components.
First, we performed a clinical evaluation of the influence of adding a venous filter to a closed loop system (Chapter 2). Forty patients were randomly assigned to be perfused with an MECC system either with or without a venous bubble trap. The main endpoint was the difference in total GME, number and volume, in the arterial line. In addition, detailed GME data (count and size) were obtained.
Chapter 3 shows how we investigated the effect of an integrated arterial filter on the air removal characteristics of an oxygenator in an MECC system. Twenty patients undergoing CABG were included and alternately randomized. GME entering and
11 leaving the device were measured; the reduction rate was the primary endpoint. Detailed GME data were also collected.
Subsequently, the air removal properties of four contemporary oxygenators with integrated arterial filter were evaluated (Chapter 4). In this prospective randomized study, twenty patients for every oxygenator were included. We assessed the reduction rates of both volume and number, and detailed GME characteristics by measuring GME entering and leaving the devices. Chapter 5 shows the air removal rates of two similarly designed oxygenators that differ in size and surface area. Detailed GME characteristics are also studied. In Chapter 6 we present the results of an in vitro study concerning the air removal rates of two different oxygenators and corresponding reservoirs after being challenged with gross air or with GME. Also the air removal rates of the complete systems are shown.
In Chapter 7 we show how we accurately measured GME entering and leaving an integrated device containing a blood pump, oxygenator and an arterial filter. Additionally, we show the effect of CO2 flushing of the CPB system prior to priming
on air removal characteristics.
Chapter 8 describes the validation of two contemporary bubble counters. We utilized an in vitro system with full control over the size, concentration, velocity and position of generated bubbles. The measurements of the bubble counters were compared with optical microscopy combined with high-speed cameras. The effect of GME on various biomarkers is evaluated in Chapter 9. In this observational study the number and size of GME entering the patient are accurately measured in 71 patients
undergoing CABG with an MECC system. Nine biomarkers for inflammatory response, endothelial damage, oxidative stress, and neurological injury were measured, and a possible correlation with GME was assessed.
Chapter 10 takes the form of a general discussion. Based on the results from the various chapters, we discuss the role and position of air removal devices (filters and oxygenators) in the CPB circuit. The impact of GME, released from the CPB circuit, on the adverse effects of cardiac surgery are also discussed.
12
REFERENCES
1. Gasz B, Benko L, Jancso G, Lantos J, Szanto Z, Alotti N, et al. Comparison of inflammatory response following coronary revascularization with or without cardiopulmonary bypass. Exp Clin Cardiol. 2004 9(1):26-30.
2. Muth CM, Shank ES. Gas embolism. N Engl J Med. 2000 342(7):476-82.
3. Vohra HA, Whistance R, Modi A, Ohri SK. The inflammatory response to miniaturised extracorporeal circulation: a review of the literature. Mediators Inflamm. 2009 :707042. 4. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation:
pathophysiology and treatment. An update. Eur J Cardiothorac Surg. 2002 02;21(2):232-44. 5. Borst C, Grundeman PF. Minimally invasive coronary artery bypass grafting: an experimental
perspective. Circulation. 1999 99(11):1400-3.
6. Barak M, Katz Y. Microbubbles: pathophysiology and clinical implications. Chest. 2005 10;128(4):2918-32.
7. Rodriguez RA, Williams KA, Babaev A, Rubens F, Nathan HJ. Effect of perfusionist technique on cerebral embolization during cardiopulmonary bypass. Perfusion. 2005 01;20(1):3-10. 8. Taylor RL, Borger MA, Weisel RD, Fedorko L, Feindel CM. Cerebral microemboli during
cardiopulmonary bypass: increased emboli during perfusionist interventions. Ann Thorac Surg. 1999 07;68(1):89-93.
9. Borger MA, Feindel CM. Cerebral emboli during cardiopulmonary bypass: effect of perfusionist interventions and aortic cannulas. J Extra Corpor Technol. 2002 03;34(1):29-33.
10. Lynch JE, Riley JB. Microemboli detection on extracorporeal bypass circuits. Perfusion. 2008 01;23(1):23-32.
11. Aboud A, Liebing K, Borgermann J, Ensminger S, Zittermann A, Renner A, et al. Excessive negative venous line pressures and increased arterial air bubble counts during miniaturized cardiopulmonary bypass: an experimental study comparing miniaturized with conventional perfusion systems. Eur J Cardiothorac Surg. 2014 45(1):69-74.
12. Simons AP, Ganushchak YM, Teerenstra S, Bergmans DC, Maessen JG, Weerwind PW. Hypovolemia in extracorporeal life support can lead to arterial gaseous microemboli. Artif Organs. 2013 37(3):276-82.
13. Rodriguez RA, Rubens F, Belway D, Nathan HJ. Residual air in the venous cannula increases cerebral embolization at the onset of cardiopulmonary bypass. Eur J Cardiothorac Surg. 2006 02;29(2):175-80.
14. Groenenberg I, Weerwind PW, Everts PA, Maessen JG. Dutch perfusion incident survey. Perfusion. 2010 25(5):329-36.
15. De Somer F. Impact of oxygenator characteristics on its capability to remove gaseous microemboli. J Extra Corpor Technol. 2007 39(4):271-3.
16. Anastasiadis K, Murkin J, Antonitsis P, Bauer A, Ranucci M, Gygax E, et al. Use of minimal invasive extracorporeal circulation in cardiac surgery: principles, definitions and potential
13 benefits. A position paper from the Minimal invasive Extra-Corporeal Technologies
international Society (MiECTiS). Interact Cardiovasc Thorac Surg. 2016 22(5):647-62. 17. Norman MJ, Sistino JJ, Acsell JR. The effectiveness of low-prime cardiopulmonary bypass
circuits at removing gaseous emboli. J Extra Corpor Technol. 2004 12;36(4):336-42. 18. Nollert G, Schwabenland I, Maktav D, Kur F, Christ F, Fraunberger P, et al. Miniaturized
cardiopulmonary bypass in coronary artery bypass surgery: marginal impact on inflammation and coagulation but loss of safety margins. Ann Thorac Surg. 2005 12;80(6):2326-32. 19. Perthel M, El-Ayoubi L, Bendisch A, Laas J, Gerigk M. Clinical advantages of using
mini-bypass systems in terms of blood product use, postoperative bleeding and air entrainment: an in vivo clinical perspective. Eur J Cardiothorac Surg. 2007 06;31(6):1070-5. 20. Camboni D, Schmidt S, Philipp A, Rupprecht L, Haneya A, Puehler T, et al. Microbubble
activity in miniaturized and in conventional extracorporeal circulation. ASAIO J. 2009 01;55(1):58-62.
21. Myers G.J., Voorhees C., Haynes R., ke B. Post-Arterial filter gaseous microemboli activity of five integral cardiotomy reservoirs during venting: An in vitro study. J Extra Corpor. 2009 03;41(1):20-7.
22. Willcox TW, Mitchell SJ. Microemboli in our bypass circuits: a contemporary audit. J Extra Corpor Technol. 2009 41(4):P31-7.
23. Potger KC, McMillan D, Ambrose M. Microbubble transmission during cardiotomy infusion of a hardshell venous reservoir with integrated cardiotomy versus a softshell venous reservoir with separated cardiotomy: an in vitro comparison. J Extra Corpor Technol. 2013 45(2):77-85.
15
CHAPTER 2
Air removal efficiency of a venous bubble trap in a minimal extracorporeal circuit during coronary artery bypass grafting.
Tamara P.A. Roosenhoff, Marco C. Stehouwer, Roel de Vroege, René Ph. Butter, Wim-Jan van Boven and Peter Bruins
16
ABSTRACT
The use of minimized extracorporeal circuits (MECC) in cardiac surgery is expanding. These circuits eliminate volume storage and bubble trap reservoirs to minimize the circuit. However, this may increase the risk of gaseous micro emboli (GME). To reduce this risk a venous bubble trap was designed. This study was performed to evaluate if incorporation of a venous bubble trap in a MECC system as compared to our standard minimized extracorporeal circuit without venous bubble trap reduces gaseous micro emboli during cardiopulmonary bypass (CPB). Forty patients were randomly assigned to be perfused either with or without an integrated venous bubble trap.
After preliminary evaluation of the data of 23 patients, the study was terminated prior to study completion.
The quantity and volume of GME were significantly lower in patients perfused with a venous bubble trap compared to patients perfused without a venous bubble trap. The present study demonstrates that a MECC system with a venous bubble trap significantly reduces the volume of GME and strongly reduces the quantity of large GME (> 500 µm). Therefore, the use of a venous bubble trap in a MECC system is warranted.
17 INTRODUCTION
Recently, a minimal extracorporeal circulation (MECC) system was developed to reduce the detrimental effects of cardiopulmonary bypass (CPB). In this system the venous reservoir and the cardiotomy reservoir were eliminated. This resulted in the reduction of priming volume, blood-air interface and artificial surface contact area. The improved biocompatibility ameliorates organ preservation and reduces transfusion of homologous blood products (1,2). However, the MECC system is a closed loop system, employing kinetically assisted venous drainage, which may increase the risk of introducing venous air. Venous air travels easily through a bypass system resulting in gaseous micro emboli (GME) in the arterial line prior to entering the patient's arterial circulation (3,4). The number of cerebral micro emboli increase in conventional extracorporeal circulation (ECC) systems during drug bolus injections, blood sampling, during low blood volume levels in the venous reservoir and infusions (5-7).
Micro emboli activate the inflammatory response and may even obstruct the blood flow in the capillary vessels, causing ischemia of the tissues (8). Consequently, these pathophysiological processes may lead to a decline in the cognitive function of the patient (9).
Less micro emboli were detected in the arterial line and in the cerebral vessels during the use of MECC systems as compared to conventional systems (10,11). However, more recently, a study on the use of a customised MECC system was terminated prior to study completion due to venous air leakage (12). Others have also raised their concerns over patient' safety by using a miniaturised extracorporeal circulation system, without a safety feature to remove venous air (13,14).
The use of an air removal device at the venous side of the MECC system could avoid air entering this system and may increase patient' safety. A venous bubble trap (VBT) was designed as air removal device for air separation in the venous line of MECC systems.
The aim of this study was to evaluate the air removing efficiency of the VBT in a MECC system during coronary bypass graft surgery (CABG) by measuring micro emboli.
18
MATERIALS AND METHODS Patients
A prospective randomised study was performed in a teaching hospital in Nieuwegein, The Netherlands. After approval from the local Medical Ethics Committee, forty patients undergoing elective revascularisation with MECC, were randomly assigned to be perfused either with VBT (VBT group) or without a VBT (control group). Initially, the study was planned as a clinical trial including a total of 40 patients.
Included were patients undergoing first time CABG with two or three vessel coronary artery disease. Excluded were emergency surgery, patients with combined surgical procedures, or when air was visually observed in the venous line during the procedure.
The MECC system
The closed loop MECC system (Figure 1) was controlled by a HL30® heart-lung
machine (Maquet, Hirrlingen, Germany) and consisted of a tip to tip heparin coated tubing system (Bioline®; Maquet), a centrifugal pump (Rotaflow®; Maquet) and an
oxygenator (Quadrox HE®; Maquet). In the VBT group a VBT 160® (Maquet) was
interconnected in the venous line before the centrifugal pump. The aortic vent line ran through a drip chamber and was connected to the VBT. During extracorporeal circulation the recirculation line on the oxygenator was constantly open leading to the sample manifold.
19 Figure 1: Schematic overview of the MECC system and the position of the sensor
probes of the bubble counter (Picture provided courtesy of Maquet, Germany).
The MECC system was primed with 500 ml and increased to 650 ml, when the VBT was included into the system. Priming solution was prepared by adding 500 ml of Haes 6% (Voluven, Fresenius Kabi, ‘s Hertogenbosch, Netherlands) into 3 L of NaCl 0.9% (Braun, Melsungen, Germany).
A level detector was located on the drip chamber in the aortic vent line and a bubble sensor (detection limit ≥ 5 mm) on the venous line. When a low-level alarm occurred or air was detected, the centrifugal pump would stop.
Venous Bubble Trap 160® (VBT)
The VBT (Figure 2) was designed for air separation in the venous line of minimized ECC circuits. In this study the VBT was interconnected in the venous line of the MECC system.
20
Figure 2: Schematic overview of flow pattern in a VBT 160 (Picture provided courtesy
of Maquet, Germany).
Air-removal by the VBT was accomplished by a combination of two principles; centrifugal flow and bubble buoyancy. The 175 µm mesh screen separates air from blood and enables removal of trapped air from both sides of the screen through the evacuation port. This air-evacuation port is connected to the autotransfusion system.
CPB-procedure
Anaesthesia was induced by infusion of midazolam (0.02-0.1 mg/kg) in combination of propofol (0.5-2 mg/kg), pancuronium (0.1 mg/kg) and fentanyl (5-10 µg/kg). Anaesthesia was maintained with a continuous propofol infusion (2-8 mg/kg/ hr), remifentanil (5-20 µg/kg/hr) and pancuronium as required.
Heparin was administered at 150 IU/kg and the aorta was cannulated with a Jostra®
arterial 24 Fr. Cannula (Maquet, Hirrlingen, Germany). The right atrial appendage was cannulated with a Jostra® venous SLIM 32/37 Fr. Cannula (Maquet). The venous
cannula was tied with a secondary snare in order to ensure an “air tight” cannulation site. In the aortic root a 7 Fr. venting needle (Medtronic, DLP®, Minneapolis, USA)
was placed.
CPB was initiated when the ACT reached a minimal level of 300 seconds measured by the Hemochron® Jr (International Technidyne Corp. (ITC), Edison, USA).
21 After aortic cross-clamping, preservation of the heart was achieved by infusion of a modified Calafiore blood cardioplegia technique as described before (15). The initial dose of potassium was 5.7 mmol/min, the second dose was 3.4 mmol/min after 20 minutes and subsequent doses were 2.6 mmol/min every 20 minutes.
During CPB the cardiac index was maintained at 2.4 L/min/m2 and acid-base
management was regulated according to the alpha-stat protocol. Mean blood pressure was maintained between 40-80 mmHg.
Shed blood was collected and processed with an autotransfusion device (Cobe Brat 2® ; Sorin Biomedica SPA, Mirandola, Italy). After CPB the residual blood in the
MECC was rinsed with 1-2 L priming solution and directed to the autotransfusion device.
After CPB, heparin was neutralised with protamine sulphate at a 1:1 ratio.
Gaseous micro emboli detection
GME were detected with the bubble counter BCC 200 (GAMPT mbH, Zappendorf, Germany). The measurements were conducted with two non-invasive sensor probes clamped on the 3/8 inch tubing. One probe was clamped on the venous tube and the other sensor probe was clamped on the tube between the centrifugal pump and the oxygenator (Figure 1). The measurement is based on a self-calibrating ultrasonic Doppler device. The BCC 200 device measures accurately the number and the size of GME, with a diameter ranging from 20 to 500 µm. The device specifies the bubbles with a diameter of more than 500 µm as ‘over range’. Particulate emboli do not influence the count results.
To avoid measurement of electronic distortion produced by diathermal coagulation, an electronic filter algorithm was used.
Statistical analysis
Quantitative variables are presented as mean ± standard deviation (SD), when appropriate unless stated otherwise. Before analysis, the data was tested for distribution according to Kolmogorov–Smirnov goodness of fit test. Continuous variables where compared by means of parametric (Student T Test). Correlation
22
between variables was tested using Spearman’s rank correlation test. Statistical analysis was performed using SPSS 10.0 (SPSS, Chicago, IL, USA).
RESULTS
After preliminary evaluation of the data of 23 patients (VBT group: n=12; control group: n=11), the study was premature discontinued due to safety concerns (see Discussion).
Demographic and intra-operative data are summarized in Table I. There were no significant differences between the groups.
Table I: Demographic and intraoperative data (data are presented as means ± SD,
except for sex (%))
Control group (n=11) VBT group (n=12) P value n 11 12 n.s. Age (y) 59.9 ± 9.5 65.8 ± 7.4 n.s. Female sex (%; n) 27 ; 3 17 ; 2 n.s. BSA (m2) 1.99 ± 0.13 1.96 ± 0.20 n.s. CPB time (min) 83.5 ± 21.5 83.0 ± 22.8 n.s.
Crossclamp time (min) 59.3 ± 16.9 61.0 ± 12.4 n.s.
Distal anastamoses (n) 4.2 ± 1.2 4.4 ± 1.0 n.s.
Minimal blood temperature (ºC)
33.7 ± 0.7 33.5 ± 0.9 n.s.
BSA = body surface area; CPB time = duration of cardiopulmonary bypass.
No air incidents took place and all patients were discharged without neurological complications. No patients were excluded during the study.
The GME measurement in the venous line (Table II) showed no significant differences between both groups. This indicates that air, considering both number and volume of GME, entering the MECC system via the venous line was comparable in both groups.
23 Table II: Results of bubble measurement in the venous line (data are presented
as means ± SD).
Control group VBT group P value
Number of GME (20-500 µm) 3525 ± 2984 3092 ± 1783 n.s. GME volume (µL) (20-500 µm) 18.28 ± 17.40 17.4 ± 14.4 n.s.
Number of ‘over range’
bubbles (n) 127.0 ± 97.3 219.6 ± 259 n.s.
Table III presents the number and volume of micro emboli measured between the centrifugal pump and the oxygenator. In both groups a significant increase of the number of GME between the centrifugal pump and the oxygenator as compared with the measurement in the venous line (Table II) was measured. Also the GME volume in the control group increased significantly from 18.3 ± 17.4 µL in the venous line to 46.8 ± 26.1 µL between the centrifugal pump and the oxygenator (P = 0.009).
Table III: Results of bubble measurement with detector probe between centrifugal
pump and oxygenator (data are presented as means ± SD).
Control group VBT group P value
Number of GME (20-500 µm) 10287 ± 3703 6886 ± 3103 < 0.05 GME volume (µL) (20-500 µm) 46.8 ± 26.1 13.4 ± 11.4 < 0.001
Number of ‘over range’
bubbles (n) 247.6 ± 241.4 7.8 ± 18.3 < 0.001
In all three micro emboli ranges, significant differences were found between the control and the study group (Table III). Both the number and volume of GME were significantly lower in the VBT group as compared to the control group. The mean
24
GME reduction deducted from the total GME volume in the control group (46.8 ± 26.1 µL) and in the VBT group (13.4 ± 11.4 µL) was 71% (P < 0.001). Also a significant reduction (97%; P<0.001) in the number of ‘over range‘ GME (> 500 µm) was found in the VBT group.
Figure 3: Histogram of GME volume (20-500 µm) with and without the VBT (data are
presented as means).
Figure 4: Relation between reduction and GME size (R2 = 0.926; P<0.01; data are
25 GME with a diameter of approximately > 400 µm were almost completely scavenged by the VBT as shown in Figure 3. GME volume reduction was significantly correlated (R²=0.926; P<0.01) with GME size ranging from approximately 20 – 400 µm as shown in Figure 4. The VBT reduced 80-100% of the bubbles with a diameter > 400 µm.
DISCUSSION
After preliminary evaluation of the obtained data, we found integration of a VBT filter into the MECC system significantly reduced GME. Moreover, we observed that the patients in the control group were exposed to a significantly higher embolic load. Particularly, we were concerned about the high number of ‘over range’ GME (>500 µm), entering the oxygenator. Although the clinical impact is unknown, we concluded that a MECC system without a VBT filter is unsafe. Therefore, we decided to
discontinue the study early.
In a conventional CPB circuit venous air is removed in the venous reservoir by buoyancy and scavenging. Since a closed loop MECC circuit has no venous reservoir, GME cannot be scavenged by buoyancy. These GME in a MECC circuit may be siphoned via the centrifugal pump and oxygenator into the arterial line. Previous studies have demonstrated that large amounts of GME during CPB lead to cognitive dysfunction (5) , coma and even mortality (16). However, the small micro emboli observed in heart valve replacement may dissolve in blood and may not cause cerebral injury (17,18).
The role of GME may be underestimated and the volume of GME causing neurologic impairment has not been completely quantified (9). The association between
cognitive dysfunction and GME originating from perfusionist interventions in a conventional CPB circuit has already been identified. (5-7). A recent study by Gerriets et al (19) showed that a complex and multifactorial problem as post operative cognitive decline (3 month outcome) could be significantly improved by a bubble trap in a CPB circuit. Furthermore, patients with higher GME counts following blood sampling showed stronger decline in a particular cognitive test (P = 0.019). The VBT is a venous bubble trap, meant to be integrated, in a MECC circuit. In the VBT a mesh screen is placed to intercept and block GME. The imparted rotational
26
spin in the blood flow in the VBT increases separation and flotation of GME. Scavenging of GME in a VBT takes place by buoyancy.
Various in vitro studies have shown that the air handling capability of closed loop systems is low compared to conventional CPB systems (3,14,20). In contrast, two recent studies reported a lower embolic load in patients perfused with a MECC system as compared to a conventional CPB system during CABG (10,11).
The results of our study show that the mean GME reduction deducted from the total GME volume was 72%. In the venous line the number of GME was in both groups lower than with the measurement between the centrifugal pump and the oxygenator. Two possible causes or a combination of these may explain this observed difference. The first may be that GME and ‘over range’ GME were fractionated into a higher number of smaller GME. This is supported by a recent study, which showed that GME entering the MECC system, also appeared in the arterial outflow, and were only fractionated into a higher number of smaller GME without a reduction of volume (10). Other studies also showed that the centrifugal pump fragment all macro emboli to micro emboli (4,21,22). Unfortunately and unexpectedly, our results show the presence of macro emboli (diameter ≥ 500 µm) distal of the centrifugal pump, mainly in the control group, indicating that macro emboli are not completely reduced to micro emboli with this particular centrifugal pump.
The other possible cause may be an effect of the location of the sensor probes. The venous sensor probe measured proximal of the location where the vent line connects with the venous line. The sensor in the venous line is not able to detect GME
entering the CPB system via the vent line. The vent line runs through a drip chamber and is connected to an integrated connector on the VBT.
Our results show that GME with a diameter of 20 to 500 µm are linear correlated (R²=0.926; P<0.01) with percentage volume reduction. This shows that the VBT gradually scavenges more micro emboli till a GME size of approximately 400 µm is reached. GME’s with a diameter >400 µm are scavenged in a range of 80-100%. We observed a 97% reduction of the number of ‘over range’ GME from an average of 247.6 in the control group to 7.8 in the VBT group. When these ‘over range’ GME are expressed as volume, assuming at least a diameter of 500 µm, the ‘over range’ volume was reduced from 16,7 µL to 0,5 µL (97%). This indicates that the VBT effectively scavenges GME during these uneventful procedures with the MECC circuit.
27 Moreover, the VBT strongly increases the safety of our closed loop circuit concerning air handling.
Limitations
The BCC 200 micro emboli detector has a limited measuring range of 20-500 µm. Micro emboli > 500 µm are not accurately measured and are categorised as ‘over range’ micro emboli. The size of an ‘over range’ emboli is estimated as 500 µm. When macro emboli and/or a high quantity of micro emboli, >1 µL/sec, pass the measuring probe, the detector is not able to quantify the emboli. These emboli disturb the correct measurement of micro emboli and consequently create a bias. Recently, two new-generation bubble counters were used in various clinical studies, the EDAC (23) and the BCC100 (10). Both instruments detect GME in different ranges, 10 µm to 12.7 mm and 10-120 µm respectively, while in our study the detection range of the BCC 200 was set at 20-500 µm. The different ranges make it difficult to compare our results with other studies.
The number of ‘over range’ GME varied greatly on a case-to-case basis, especially on the measurement between the centrifugal pump and the oxygenator: n = 247.6 ± 241.4. The strong variance was probably caused by different air related events such as perfusionist interventions (i.e. blood sampling, administration of medication or volume) or by the volume of residual air in the venous cannula after connection to the CPB circuit (24).
CONCLUSION
The results of the present study demonstrate that a VBT integrated in a MECC system significantly reduces the volume of gaseous micro emboli (20 –500 µm) by 71%. Large GME (> 500 µm) are for the greater part (97%) scavenged by the VBT. Therefore, the use of a VBT in a closed loop system is strongly advised and may further contribute to patient safety during CPB.
28
REFERENCES
1. Gerritsen WB, van Boven WJ, Wesselink RM et al: Significant reduction in blood loss in patients undergoing minimal extracorporeal circulation. Transfus Med. 2006;16:329-334. 2. Wiesenack C, Liebold A, Philipp A et al: Four years' experience with a miniaturized
extracorporeal circulation system and its influence on clinical outcome. Artif Organs. 2004;28:1082-1088.
3. Norman MJ, Sistino JJ, Acsell JR: The effectiveness of low-prime cardiopulmonary bypass circuits at removing gaseous emboli. J Extra Corpor Technol. 2004;36:336-342.
4. Jones TJ, Deal DD, Vernon JC et al: How effective are cardiopulmonary bypass circuits at removing gaseous microemboli? J Extra Corpor Technol. 2002;34:34-39.
5. Borger MA, Peniston CM, Weisel RD et al: Neuropsychologic impairment after coronary bypass surgery: effect of gaseous microemboli during perfusionist interventions. J Thorac Cardiovasc Surg. 2001;121:743-749.
6. Taylor RL, Borger MA, Weisel RD et al: Cerebral microemboli during cardiopulmonary bypass: increased emboli during perfusionist interventions. Ann Thorac Surg. 1999;68:89-93.
7. Rodriguez RA, Williams KA, Babaev A et al: Effect of perfusionist technique on cerebral embolization during cardiopulmonary bypass. Perfusion. 2005;20:3-10.
8. Muth CM, Shank ES: Gas embolism. N Engl J Med. 2000;342:476-482. 9. Barak M, Katz Y: Microbubbles: pathophysiology and clinical implications. Chest.
2005;128:2918-2932.
10. Perthel M, Kseibi S, Sagebiel F et al: Comparison of conventional extracorporeal circulation and minimal extracorporeal circulation with respect to microbubbles and microembolic signals. Perfusion. 2005;20:329-333.
11. Liebold A, Khosravi A, Westphal B et al: Effect of closed minimized cardiopulmonary bypass on cerebral tissue oxygenation and microembolization. J Thorac Cardiovasc Surg.
2006;131:268- 276.
12. Nollert G, Schwabenland I, Maktav D et al: Miniaturized cardiopulmonary bypass in coronary artery bypass surgery: marginal impact on inflammation and coagulation but loss of safety margins. Ann Thorac Surg. 2005;80:2326-2332.
13. Huybregts RM, Veerman DP, Vonk AB et al: First clinical experience with the air purge control and electrical remote-controlled tubing clamp in mini bypass. Artif Organs. 2006;30:721-724. 14. Mitsumaru A, Yozu R, Matayoshi T et al: Efficiency of an air filter at the drainage site in a
closed circuit with a centrifugal blood pump: an in vitro study. ASAIO J. 2001;47:692-695. 15. Calafiore AM, Mezzetti A, Bosco G et al: Intermittent antegrade warm blood cardioplegia. Ann
Thorac Surg. 1995;59:398-402.
16. Mitchell S, Gorman D: The pathophysiology of cerebral arterial gas embolism. J Extra Corpor Technol. 2002;34:18-23.
29 17. Kofidis T, Fischer S, Leyh R et al: Clinical relevance of intracranial high intensity transient
signals in patients following prosthetic aortic valve replacement. Eur J Cardiothorac Surg. 2002;21:22-26.
18. Nadareishvili ZG, Beletsky V, Black SE et al: Is cerebral microembolism in mechanical prosthetic heart valves clinically relevant? J Neuroimaging. 2002;12:310-315.
19. Gerriets T, Schwarz N, Sammer G et al: Protecting the brain from gaseous and solid micro-emboli during coronary artery bypass grafting: a randomized controlled trial. Eur Heart J. 2010; 31;360-368.
20. Matayoshi T, Yozu R, Morita M et al: Development of a completely closed circuit using an air filter in a drainage circuit for minimally invasive cardiac surgery. Artif Organs. 2000;24:454-458.
21. LaPietra A, Grossi EA, Pua BB et al: Assisted venous drainage presents the risk of undetected air microembolism. J Thorac Cardiovasc Surg. 2000;120:856-862. 22. Rider SP, Simon LV, Rice BJ et al: Assisted venous drainage, venous air, and gaseous
microemboli transmission into the arterial line: an in-vitro study. J Extra Corpor Technol. 1998;30:160-165.
23. Win KN, Wang S, Undar A: Microemboli generation, detection and characterization during CPB procedures in neonates, infants, and small children. ASAIO J. 2008;54:486-490. 24. Rodriguez RA, Rubens F, Belway D et al: Residual air in the venous cannula increases
cerebral embolization at the onset of cardiopulmonary bypass. Eur J Cardiothorac Surg. 2006;29:175-180.
31
CHAPTER 3
Clinical evaluation of air removal characteristics of an oxygenator with integrated arterial filter in a minimal extracorporeal circuit.
Marco C. Stehouwer, Chris Boers, Roel de Vroege, Johannes C. Kelder , Alaaddin Yilmaz , and Peter Bruins.
32
ABSTRACT
Minimized extracorporeal circuits (MECC) in cardiac surgery are an important effort to increase the biocompatibility of cardiopulmonary bypass during coronary artery bypass grafting (CABG). These circuits eliminate volume storage reservoirs and bubble traps to minimize the circuit. However, the reduction of volume may increase the risk of gaseous micro emboli (GME). The MECC system as used by our group consists of a venous bubble trap, centrifugal pump and an oxygenator. To further reduce the risk of introducing GME an oxygenator with integrated arterial filter was developed within the concept of minimal volume and foreign surface. We studied the air removal characteristics of this oxygenator with and without integrated arterial filter. The quantity and volume of GME were accurately measured at both the inlet and outlet of the devices.
Our results showed that integration of an arterial filter into this oxygenator increased GME reducing capacity from 69.2% to 92%. Moreover, the impact of an arterial filter on the exact size-distribution of GME entering the arterial line was obtained.
The present study demonstrates that a MECC system and oxygenator with integrated arterial filter reduces the volume and size of gaseous micro emboli significantly. The use of an integrated arterial filter in a MECC system may protect the patient for the deleterious effects of CPB and may further improve patient safety.
33 INTRODUCTION
Cannulation, drug administration, blood sampling and various components of the cardiopulmonary bypass (CPB) circuit are potential sources of gaseous micro-emboli (GME) during on-pump cardiac surgery (1-3). Introduction of GME into the arterial
line of a CPB circuit may lead to cognitive decline and adverse outcome (4,5). Arterial filters are incorporated in conventional bypass circuits as a safeguard for
gross air and may reduce the number of GME measured in the arterial line (6,7). A 40 µm arterial filter reduces the number of GME by 50-73%, depending on the GME-diameter (8). Gerriets et al, (9) even demonstrated a neuroprotective effect by using an arterial filter.
Miniaturized extracorporeal circuits (MECC) have been developed to reduce both blood contact surface area and priming volume. In this development process, air removal components of the CPB circuit, such as venous reservoirs and even arterial filters, have been omitted. In case of accidental gross air introduction, a closed loop system may have the risk of less efficient air handling as compared to conventional systems (10). Accordingly a venous bubble trap (VBT) with minimal priming volume (160ml) was developed. This VBT scavenges gaseous macroemboi (> 500 µm) almost completely (11) and was therefore incorporated in our MECC system for daily use to improve patient safety.
A newly developed oxygenator with integrated arterial filter reduces surface area and priming volume even further, while maintaining circuit simplicity. Now the question arises if integration of this arterial filter in combination with a VBT has additional value on microemboli reduction.
The aim of this study was to assess the air removal characteristics of this new oxygenator compared to the same oxygenator without integrated arterial filter in a MECC system during coronary bypass graft surgery (CABG) by measuring number, size and total volume of GME.
MATERIALS AND METHODS Patients
A prospective randomised study was performed in a teaching hospital in Nieuwegein, The Netherlands. After approval from the local Medical Ethics Committee, twenty
34
patients undergoing elective revascularisation with MECC, were alternately assigned to be perfused either with an oxygenator with (Oxygenator+AF group) or without (Oxygenator group) an integrated arterial filter.
Included were patients undergoing first time CABG with two or three-vessel coronary artery disease. Excluded were emergency surgery, patients with combined surgical procedures, or when air was visually observed in the venous line during the procedure.
The MECC system
The closed loop MECC system was controlled by a HL30® heart-lung machine
(Maquet, Hirrlingen, Germany) and consisted of a tip-to-tip heparin coated tubing system (Bioline®; Maquet ). In the venous line a Venous Bubble Trap® (VBT) was
integrated and blood flow was created with a centrifugal pump (Rotaflow®; Maquet). In
the Oxygenator group a Quadrox-i Adult® (Maquet) and in the Oxygenator+AF group
a Quadrox-i Adult with integrated arterial filter® (Maquet) was used. The aortic vent
line ran through a drip chamber and was connected to the VBT. During
extracorporeal circulation the recirculation line on the oxygenator or on the integrated arterial filter leading to the sample manifold was constantly open.
The MECC system was primed with either 650 ml (Oxygenator group) or 765 ml (Oxygenator+AF group). Priming solution was a combination of 500 ml of Haes 6% (Voluven, Fresenius Kabi, ‘s Hertogenbosch, Netherlands) and 3 L of NaCl 0.9% (Braun, Melsungen, Germany).
A level detector was located on the drip chamber in the aortic vent line and a bubble sensor (detection limit ≥ 5 mm) on the venous line. When a low level alarm occurred or air was detected, the centrifugal pump would stop.
Quadrox-i Adult® with and without integrated arterial filter
The quadrox-i is an oxygenator and a heat exchanger equipped with a microporeus membrane. The priming volume is 215 ml. The Quadrox-i with integrated arterial filter has a priming volume of 330 ml. The integrated arterial filter is comprised of 4.5 parallel filter cassettes with a pore size of 40 µm. After diffusing through the filter medium, the blood flows through the individual cassettes towards the common outlet, which is located at the bottom of the housing. The integrated filter approach leads to:
35 a minimized priming volume, less blood foreign surface contact and a more compact design.
CPB-procedure
Anaesthesia was induced by infusion of midazolam (0.02-0.1 mg/kg) in combination with propofol (0.5-2 mg/kg), pancuronium (0.1 mg/kg) and fentanyl (5-10 µg/kg). Anaesthesia was maintained with a continuous propofol infusion (2-8 mg/kg/hr) and remifentanil (5-20 µg/kg/hr).
After heparinization (150 IU/kg) the aorta was cannulated with a Jostra® arterial 24 Fr.
Cannula (Maquet, Hirrlingen, Germany). The right atrial appendage was cannulated with a Jostra® venous SLIM 32/37 Fr. Cannula (Maquet). The venous cannula was
tied with a secondary snare in order to ensure an “air tight” cannulation site. In the aortic root a 7 Fr. venting needle (Medtronic, DLP®, Minneapolis, USA) was placed.
CPB was initiated when the ACT was 300 seconds measured by the Hemochron® Jr
(International Technidyne Corp. (ITC), Edison, USA).
During CPB the nasopharyngeal temperature was maintained at 32-34 °C. After aortic cross-clamping, preservation of the heart was achieved by infusion of a modified Calafiore blood cardioplegia technique (12). The initial dose of potassium was 5.7 mmol/min, and was followed by a second dose of 3.4 mmol/min after 20 minutes with subsequent doses of 2.6 mmol/min every 20 minutes.
During CPB the cardiac index was maintained at 2.4 L/min/m2 and acid-base
management was regulated according to the alpha-stat protocol. Mean blood pressure was maintained between 40-80 mmHg.
After the initial blood cardioplegia dose and during rewarming, the pO2 of blood
samples were measured by a blood-gas analyzer (Bayer, Rapidlab 855, Tarrytown, NY, USA).
Shed blood was collected and processed with an autotransfusion device (Cobe Brat 2® ; Sorin Biomedica SPA, Mirandola, Italy). After CPB the residual blood in the
MECC was rinsed with 1-2 L priming solution and directed to the autotransfusion device.
36
Gaseous micro emboli detection
GME were detected with the bubble counter BCC 200 (GAMPT mbH, Zappendorf, Germany). The measurements were conducted with two non-invasive sensor probes clamped on the 3/8 inch tubing. The probes were clamped on the inflow and outflow tubing of the oxygenator. The measurement is based on a self-calibrating ultrasonic Doppler device. The BCC 200 device measures accurately the number and the size of GME, with a diameter ranging from 20 to 500 µm. The device specifies the bubbles with a diameter of more than 500 µm as ‘over range’. Particulate emboli do not influence the count results. Data were collected and cumulated during the complete CPB.
To avoid measurement of electronic distortion produced by diathermal coagulation, an electronic filter algorithm was used.
Statistical analysis
Quantitative variables are presented as mean ± standard deviation (SD), when appropriate unless stated otherwise. Normal distribution of the quantitative variables was assessed visually. Continuous variables were compared by means of the Student t-Test or Mann-Whitney and Wilcoxon tests when appropriate. Categorical variables were compared by means of the Chi-square test.
A 95 % cut-off value, introduced by us, was defined as the smallest diameter of GME, where 95 % reduction was observed.
% Reduction is calculated by the formula: % Reduction = [1-GMEout/GMEin]*100.
37 RESULTS
Demographic and intra-operative data are summarized in Table I. There were no significant differences between the groups.
Table I: Demographic and intraoperative data (data are presented as means ± SD,
except for sex (%)).
Oxygenator group Oxygenator+AF
group p value n 10 10 n.s. Age (y) 67 ± 7 62 ± 9 n.s. Female sex (%; n) 20 ; 2 20 ; 2 n.s. BSA (m2) 1.96 ± 0.21 1.99 ± 0.21 n.s. CPB time (min) 83 ± 16 98 ± 32 n.s.
Cross-clamp time (min) 53 ± 13 64 ± 23 n.s.
Distal anastomoses (n) 4.2 ± 1.2 4.3 ± 1.2 n.s.
Mean pO2 (mmHg) 22.5 ± 5.7 22.5 ± 6.4 n.s.
Minimal blood temperature (ºC)
34.1 ± 0.6 34.4 ± 0.2 n.s.
BSA = body surface area; CPB time = duration of cardiopulmonary bypass.
One patient from the Oxygenator+AF group was excluded because of massive air entering the system through the venous line. The air was evacuated through the VBT air filter and the procedure was completed without complications. The patient was replaced to keep sample size equal. In the other patients no air incidents took place and all patients were discharged without neurological complications.
For both groups the obtained data with respect to GME are listed in Table II. Within group analysis demonstrated in number of GME, the GME volume and number of ‘over range’ bubbles range a significant decrease behind both oxygenator-devices. Only the number of GME normalized for CPB time was not significantly decreased in the oxygenator in contrast with the oxygenator with integrated filter.
38
Table II: Results of GME measurement in the Oxygenator and Oxygenator+AF
groups (data are presented as means ± SD); CPB time = duration of cardiopulmonary bypass. Oxygenator Oxygenator + AF In Out p value (*) In Out p value (*) Number of GME (20-500 µm) 9806 ± 5420 7893 ± 4553 0.0098 12306 ± 11018 9653 ± 8996 0.0273 Number of GME/ CPB time (n/min) 100 ± 53 91 ± 49 0.0839 132 ± 16 93 ± 53 0.0039 GME volume (µL) (20-500 µm) 25.4 ± 14.2 7.8 ± 8.1 0.0020 35.5 ± 26.3 3.1 ± 3.0 0.0020 Number of ‘over range’ bubbles (n) 97.0 ± 72.0 0.1± 0.3 0.0020 168.2 ± 163.2 4.1± 12.6 0.0190 (*) Wilcoxon test
In all three micro emboli ranges, including number of GME normalized for CPB time, no difference was found between both groups considering GME entering the oxygenators. Both number of GME and number of GME normalized for CPB time showed no significant difference between both devices. The GME volume behind the oxygenator with arterial filter (3.1 ± 3.0) was marginally lower (P = 0.052) than in the oxygenator group (7.8 ± 8.1). No significant difference was found between the number of ‘over range’ bubbles behind the oxygenator (0.1 ± 0.32) or the oxygenator with integrated filter (4.1 ± 12.6).
In Figure 1 the mean % reduction is presented.
The reduction of the number of GME was equal in both groups, 17.9 ± 17.3 % in the Oxygenator group and 19.8 ± 27.7 % in the Oxygenator+AF group (p=0.44). The reduction of the GME-volume of the Oxygenator+AF group was significantly better than in the Oxygenator group (92.0 ± 5.3 vs 69.2 ± 16.6, p=0.002).
39 Figure 1: Reduction of GME (%) in the Oxygenator and Oxygenator+AF group (data
are presented as means ± SD).
‘Over range’ GME were almost completely reduced in both the Oxygenator and the Oxygenator+AF group, respectively 100.0 % and 99.7 %.
In Figure 2 shows that the distribution of size of the number of GME entering both devices seems rather similar. However, the distribution of number of microemboli leaving both devices showed different distributions.
Figure 2: Distribution of number of GME (20-500 µm) A: Oxygenator; B:
Oxygenator+AF (data are presented as means).
40
From the number of GME and their diameter, the volume distribution curve could be calculated as shown in Figure 3. The distributions of GME volume of both groups show more detail about the GME entering (in) and leaving (out) the devices.
Figure 3: Distribution of GME volume (20-500 µm) A: Oxygenator; B: Oxygenator+AF
(data are presented as means).
Figure 4: Relation between reduction and GME size (The 95% cut off value is
showed as vertical lines): A: Oxygenator; B: Oxygenator+AF (data are presented as means).
To make interpretation of the data more clear, the % reduction per GME size is shown in Figure 4. In the Oxygenator group GME from 20 to circa 160 µm were not
A B
41 reduced, but apparently generated. In the Oxygenator+AF group the same
phenomenon was observed with GME from 20 to circa 90 µm. The 95 % cut-off for the Oxygenator group was 318 µm and for the Oxygenator+AFgroup 165 µm.
DISCUSSION
Both the oxygenator with and without integrated arterial filter reduced the volume of GME and ‘over range’ bubbles. In addition, integration of an arterial filter in an oxygenator led to a more significant reduction of both size and volume of GME as compared to a oxygenator without arterial filter. Moreover, for the first time we were able to visualize the impact of an arterial filter on the exact size-distribution of GME entering the aortic line and subsequently contributing to the embolic load of the patient by the use of the new-generation bubble counter that quantifies and qualifies GME accurately, and provides insight in detailed GME distribution.
Originally, the MECC system consisted only of a centrifugal pump and an oxygenator (13,14). With this MECC system a reduction of priming volume of approximately 600 mL was obtained as compared to a conventional ECC system with a priming volume of 1500-2000 mL. The combined efforts of warm blood cardioplegia, transfusion of processed shed mediastinal blood, reduction of blood-air contact and decreased foreign surface contact may lead to an improved clinical outcome after cardiothoracic surgery (15).
Despite the lack of air removal components various studies showed that during CPB the amount of gaseous emboli entering the patient decreased when compared to conventional CPB (16,17). This could either be caused by the total closed aspect of the MECC system, or by the lower initial air entrapment in the venous line during connection of the mini-system (18).
A closed loop system as in mini systems may be more vulnerable to accidental gross air introduction (10,13,19) . For this reason a VBT was developed as a safety device. A recent study (11) from our group showed that a VBT in a MECC system reduced the volume of GME (20-500 µm) for 71%. ‘Over range’ GME were scavenged for 97% by this venous filter.
42
Our results showed that although our current MECC system is equipped with a VBT, GME still could reach the oxygenator devices. We showed that integration of an arterial filter into this oxygenator increased GME reducing capacity from 69.2% to 92%.
Two recent in vitro studies showed corresponding GME reduction rates of 89-95% by the same oxygenator with integrated arterial filter (20) , or by a combination of the oxygenator with a separate arterial filter (21). Recently, Jirschik et al (22) observed a comparable GME volume reduction of 75% with the use of this oxygenator without an integrated arterial filter.
However, the reduction of number of GME in the oxygenator with arterial filter was 17.9%, while the GME volume reduction was 92%. This may be explained by the phenomenon that GME can be fractionated into a higher number of smaller GME. This explanation is supported by a recent study, which showed that GME entering the MECC system also appeared in the arterial outflow and were only fractionated into a higher number of smaller GME without reduction of the total volume (23). This fractionation phenomenon can be observed in our obtained distribution of volume and percentage reduction graphs. Especially in the percentage reduction graphs the ‘generation’ of small GME is visualized by the negative reduction rates as found in the smaller GME diameter range. Therefore, in our opinion measuring GME volume instead of number of GME is of additional value.
Also the use of number of GME normalized for CPB time is in our opinion not a reliable parameter because of this fractionation of GME and also the cause of GME generation during CPB. GME generation during CABG seems to be correlated by perfusionist interventions, rather than surgical interventions (2,3), which can result in longer CPB times caused by surgical technique while no more perfusionist
interventions occur.
Interpretation of our data, based on detailed reduction characteristics made it possible to introduce a new parameter, the 95% cut-off value. The 95% cut-off value was defined as the smallest diameter of GME, where 95% reduction was observed. The cut-off for the oxygenator group without integrated arterial filter was 318 µm and for the oxygenator group with integrated arterial filter 165 µm. Although, the size of GME causing pathological changes is not known, bigger GME may be prone to worsen ischemic damage. GME can block small arteries, sizing 30-60 µm (4). Their
43 dissolution time increases with bubble size according to a formula (24), based on theoretical and experimental results, GME’s with a diameter of 318 µm and a 165 µm will be absorbed in approximately 47 min and 12.5 min, respectively. This means that the integrated arterial filter is able to reduce the ischemia time, caused by GME with approximately 35 minutes.
The GME size distribution graph also showed different characteristics of GME entering both devices. This may be explained by the oxygenator with integrated arterial filter reduces GME more adequate resulting in more GME re-entering the venous side of the MECC circuit through the recirculation line on the oxygenator. Gerriets et al (9) showed that a complex and multifactorial problem as postoperative cognitive decline after 3 months could be improved by the use of an arterial filter. Our results show that this may be merely an effect of decreased bubble size as caused by an arterial filter than reduction of total bubble volume. Besides the possible negative effect of GME on cognitive functioning, GME may induce an inflammatory response and may damage endothelial cells leading to ischemia injury of end-organs (5). Therefore, reducing size and volume of GME by an arterial filter may contribute to the protection of the cardiac patient against the adverse effects of CPB.
The advantage of decreased hemodilution as obtained with MECC may contribute to better organ protection, improved neurological outcome (25,26) and a reduction of blood transfusion (13,14,27). Compared with the original MECC system (circa 600 ml), the addition of both the VBT (160 ml) and the integrated arterial filter (115 ml) will lead to a total priming volume of circa 875 ml. Although we do not know the effect of slightly higher hemodilution on outcome, we argue that the reduction of GME size (95% cut-off) entering the circulation could justify the use of an arterial filter. Limitations
This study has some limitations. Caution should be taken when detailed bubble distribution is used.
We are aware that the error of measurement of GME diameter is not known but we interpreted the measurement error as random noise as seen in the distribution graphs and concluded that this does not invalidate our computations and inferences thereof since ‘ only ‘ the precision was impaired.
44
The BCC200 calculates the GME volume on the hypothesis that the bubble is a perfect sphere. Especially with increased diameters this hypothesis becomes less and less true and may result in impaired precision.
De Somer et al (28) showed that the BCC200 bubble counter overestimates sizes of micro bubbles more than 200%. However, limitation of their study was that only one apparatus was tested and that this study was carried out not in routine care of the patient but during a worst-case scenario, i.e. high embolic loads. The concentration of bubbles was probably to high since the BCC200 has a limitation of measuring more than 200 bubbles/s as mentioned in a comment of Schultz et al (29).
Nevertheless, the article of De Somer et al raises concerns about validation of bubble counter devices and stresses the need for independent research on GME validation.
CONCLUSION
Both the oxygenator with and without integrated arterial filter reduced the volume of GME significantly. Although the oxygenator with integrated arterial filter reduces the volume of GME more than the oxygenator without integrated arterial filter. In both groups the ‘over range’ bubbles were almost completely removed by the devices. An arterial filter may protect the patient for the deleterious effects of GME by reducing both the volume and the size of GME that contributes to the embolic load. Therefore, the use of the integrated arterial filter during CABG with a MECC could be justified.
An important secondary conclusion is that with the aid of the new-generation bubble counters detailed GME distributions can be obtained. The use of GME volume instead of number of GME provides more detailed information on reducing
characteristics of CPB circuit components, but awaits empirical evidence on clinical relevance.
45 REFERENCES
1 Borger MA, Peniston CM, Weisel RD, Vasiliou M, Green RE, Feindel CM. Neuropsychologic impairment after coronary bypass surgery: effect of gaseous microemboli during perfusionist interventions. J Thorac Cardiovasc Surg. 2001;121(4):743-749.
2 Taylor RL, Borger MA, Weisel RD, Fedorko L, Feindel CM. Cerebral microemboli during cardiopulmonary bypass: increased emboli during perfusionist interventions. Ann Thorac Surg. 1999;68(1):89-93.
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