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Eur J Cardiothorac Surg 2000;17:729-736
© 2000 Elsevier Science NL
a Department of Cardiothoracic Surgery, University of Essen, Hufelandstrasse 55, 45147 Essen, Germany
b Department of Physiology, University of Munich, Munich, Germany
c Department of Anaesthesiology, German Heart Center Munich, Munich, Germany
d Department of Cardiothoracic Surgery, German Heart Center Munich, Munich, Germany
Corresponding author. Tel.: +49-201-723-3151; fax: +49-201-723-5931
e-mail: parwis.massoudy{at}uni-essen.de
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Abstract |
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 Top Abstract 1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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Key Words: Extracorporeal circulation • Drew technique • Coronary artery bypass grafting • Pulmonary inflammatory response • Cytokine • Adhesion molecule
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1. Introduction |
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TopAbstract1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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Extracorporeal circulation can also be performed using the patients lungs as physiologic oxygenators during the operation. This procedure is named after Charles Drew [5–7]. Surgical procedure is different in that right and left atrium, pulmonary artery and aorta have to be cannulated. Thereafter, the pulmonary and the systemic circulation are perfused separately. Even during cardiac ischemia, perfusion of the lungs is maintained. Recent data of our group show that postoperative lung function is significantly improved in these patients, which leads to shorter extubation times. Consequently, the length of stay on the intensive care unit is also reduced [8]. At the same time there is a considerable reduction of the systemic inflammatory response, suggesting the use of an oxygenator as one of the main reasons for this phenomenon.
Recently, we have shown that significant inflammatory changes occur during reperfusion of the lungs in patients undergoing coronary artery bypass grafting (CABG) with conventional CPB [3]. The aim of the present study was to examine these changes in CABG patients undergoing CABG with bilateral extracorporeal circulation.
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2. Subjects and methods |
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TopAbstract1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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2.1. Surgery
All patients underwent CABG with CPB using roller pumps (Stöckert, München, Germany) and disposable membrane oxygenators (Dideco, Mirandola, Italy). Anesthesia was conducted as a total intravenous technique as previously described [9]. Aprotinin (Trasylol, Bayer, Leverkusen, Germany) was given according to the Hammersmith protocol (total dose 6 million KIU). CPB was instituted at a flow rate of 2.4 l/min per m2 BSA after systemic heparinization. Perfusion pressure during CPB was maintained between 50 and 70 mmHg in both groups. The body temperature was cooled to 28–30°C (moderate hypothermia) and 1000 ml of 4°C cold Bretschneider solution (Custodiol, Köhler Chemie, Alsbach-Hähnlein, Germany) was applied as antegrade cardioplegia after clamping of the aorta. Before termination of CPB, an infusion of dopamine (3–5 µ/kg per min) was used as first line drug in both groups. After termination of CPB its infusion rate was adapted according to the patient's circulatory state. A cardiac index 
2.3 l/min per m2 and a mean arterial pressure 60 mmHg were the targets. Protamine was given to neutralize anticoagulation according to the patient's ACT.
2.2. Drew perfusion technique
After systemic heparinization the aorta was cannulated, then a two-stage venous cannula was inserted into the right atrium and the inferior caval vein (Two stage, Stöckert, Munich, Germany). The main pulmonary artery was cannulated approximately 2 cm distal the pulmonary valve with a wire-reinforced cannula (Stöckert). Right heart bypass was then started and a 28–32-gauge wire-wound cannula (Stöckert) was inserted into the left atrium via a teflon-reinforced purse-string suture at the junction of the right superior pulmonary vein or between the aorta and the superior caval vein. Left-heart bypass was then started and the patient cooled to 28–30°C rectal temperature under the conditions of bilateral extracorporeal circulation. Controlled ventilation of the lungs was maintained throughout the procedure. Alveolar ventilation of the lungs during bilateral extracorporeal circulation was reduced as temperature decreased. Continuous measurement of blood gases and acid–base balance made control of ventilation and oxygenation easy. The flow of the right-heart bypass was kept at 0.2–0.3 l/min higher than for the left-sided circulation. By opening of a shunt, balancing of the levels in the two reservoirs was facilitated. After completion of distal anastomoses, rewarming of the patient, and as soon as the heart was beating sufficiently and performing pressure–volume work, the right-sided cannulas were removed. Thereafter left-heart bypass was terminated and the respective cannulas removed.
2.3. Flow cytometry
Flow cytometry was performed as previously described [9]. In brief, for analysis of leukocytes, 100-µl aliquots of the blood samples were immediately mixed with 1 ml FACS lysing solution (Becton Dickinson, Heidelberg, Germany). Leukocytes were pelleted and then double-stained with FITC-labeled anti-CD41 antibodies (Serotec, Kidlington, UK) and PE labeled anti-CD11b antibodies (Exalpha, Boston, MA). The measurement of the platelet marker CD41 on leukocytes served to determine the percentages of neutrophils and monocytes carrying platelets.
For analysis of platelets, 100 µl of blood and 1 ml Cellfix (Becton Dickinson) were employed. After centrifugation the pellet was incubated with antibodies against CD41 (FITC-labeled, Serotec) and CD62 (PE-conjugated, Harlan Seralab, Crawley Down, UK).
Flow cytometry was performed with a FACScan and Lysis II software (Becton Dickinson). The mean fluorescence intensity was taken as a measure of antibody binding. Reproducibility of flow cytometry was ensured by regular measurement of calibrated standards. The non-specific background was quantified by measurement of the fluorescence intensity of samples labeled with non-binding, isotype-matched antibodies, and subsequently subtracted. Results were calculated as relative fluorescence units.
2.4. Cytokines
For analysis of cytokines, blood specimens were collected into ammonium-heparin-tubes (Sarstedt, Nümbrecht, Germany). Plasma samples were stored frozen at -20°C until assayed within batches. Interleukin (IL)-6 and IL-8 were measured using a solid phase, two-site chemiluminescent enzyme immunometric assay (Immulite system, Diagnostic Products Corp., Los Angeles, CA).
2.5. Statistics
All results are expressed as mean±SEM. Student's t-test for paired samples was used to evaluate the differences between the two groups. A difference on a two-tailed test was considered as statistically significant for P<0.05. No within-group comparison was made regarding results at different time points.
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3. Results |
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TopAbstract1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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4. Discussion |
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TopAbstract1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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In the present study, using the Drew circulation technique more or less equal cytokine levels in right atrium and pulmonary vein were observed after declamping of the aorta. In addition, the retention of activated leukocytes and leukocyte–platelet coaggregates was attenuated. These changes speak for a reduced pulmonary inflammatory response under the drew perfusion technique.
The cellular origin of cytokines during pulmonary passage is unclear. With 8 and 20% leukocytes trapped within the pulmonary circulation before and after ischemia, respectively, these blood cells may well be a source of the observed cytokine release [10]. IL-6 and IL-8 have been shown to be produced by a variety of leukocyte subsets [11]. Whether lung tissue itself can prove responsible for the observed cytokine production is unclear. IL-8 is known to be localized, preformed, in the Weibel–Palade bodies of the vascular endothelial cells, from where it can be released upon stimulation [12]. Thus, less contact between activated leukocytes and the pulmonary vascular endothelium, as indicated by less retention of these cells in the lungs of patients perfused with the Drew technique, may be responsible for less cytokine release by the endothelium. The cytokines themselves play a pivotal role by increasing the expression of cell surface receptors [13]. In the present study, absolute cell counts in right atrium and pulmonary vein were not determined. Whether reduced cytokine levels are accompanied by less leukocyte retention has to be the subject of future investigation.
One important difference between the two perfusion techniques is that contact activation of blood elements by the artificial surface of a machine oxygenator is prevented in the case of the Drew technique. The tubing system with its artificial surface persists, its length even being doubled compared to the conventional CPB technique because of bilateral circulation with four instead of two cannulas.
Another main difference between conventional CPB and the Drew technique is the continuous perfusion of the lungs during cardiac ischemia in the latter. With the Drew technique, the lungs do not undergo reperfusion as does the heart. In contrast, in routine CPB there is almost no antegrade flow over the pulmonary artery into the lungs and the amount of blood entering the lungs over bronchial artery flow is negligible. Thus, with the routine technique, after declamping of the aorta and termination of CPB, the reperfusion of the lungs may lead to the complex of leukocyte–endothelial interaction, sequestration of leukocytes, release of oxygen reactive compounds, subsequent tissue damage and organ dysfunction, known as reperfusion damage [14].
Earlier studies have shown that diminished pulmonary blood flow during total CPB results in postoperative impairment of vascular endothelial function [15]. At the same time, as an indicator of endothelial dysfunction, an inability to release nitric oxide is observed [16]. When nitric oxide is supplemented exogenously with the beginning of reperfusion, a considerable reduction of the systemic inflammatory response is achieved [9]. Taken together, in routine CPB the two main stimuli for an inflammatory reaction are the use of an oxygenator and the reperfusion of the previously excluded lungs, which are the only organs to receive the entire cardiac output.
In the late 1950s, cardiac surgeons were concerned about the high mortality in experimental series and in the early clinical experience. The problem seemed to be related to the oxygenators with their direct blood–gas interface [5]. The use of an oxygenator implies the application of high-dose heparin. However, even under this regimen the generation of thrombin by activation of the coagulation cascade can not be completely inhibited [17]. Using the Drew technique, the degree of contact activation is supposed to be considerably reduced [8]. During routine CPB thrombin levels are increased, which is considered to be due to contact activation [17]. Thrombin is involved in the activation of leukocytes and platelets and acts on the endothelium to release a variety of vasoactive and inflammatory mediators [18]. In the present study, thrombin was not determined. Further studies have to show whether lower cytokine levels are accompanied by less thrombin production in patients operated with the Drew technique.
Reperfusion induces a number of pathophysiological changes, although it is necessary to re-establish organ function [14]. In the lungs, neutrophils have been shown to be sequestered [10]; at the same time, increased levels of pro-inflammatory mediators are observed [3]. The sequestration of neutrophils leads to the release of proteolytic enzymes and toxic oxygen radicals [17]. The consequence is a swelling of endothelial cells, fluid and plasma extravasation [19]. In the case of the lungs, alveolar pneumocytes disrupt, alveoli fill with inflammatory debris and red blood cells, finally leading to severe pulmonary dysfunction [20]. The clinical picture that follows can be barely noticeable symptoms leading to lethal respiratory failure [8]. In general, about 1.7% of CPB patients develop adult respiratory distress syndrome (ARDS). But when acute severe lung injury occurs, mortality is high [17]. Recent studies have shown an activation of both humoral and cellular components of the inflammatory system in response to CPB [21]. Interestingly, not only the peak of the systemic inflammatory response takes place 2–4 h after termination of CPB [22], but also the slope of the increase observed after termination of CPB is much steeper than that during CPB [22]. Thus, reperfusion of the previously ischemic heart and lungs seems to promote this phenomenon. In fact, after release of the aortic cross-clamp the production of inflammatory mediators and cellular activation has been shown during reperfusion of the heart [4]. However, because only about 5% of the cardiac output perfuses the heart, the cardiac inflammatory reaction would not be expected to lead to a considerable increase of systemic levels of inflammatory mediators. In contrast, the entire cardiac output passes the lungs as soon as CPB is terminated. With ongoing pulmonary cytokine release even after termination of CPB, the lungs would thus be a major promoter of the systemic inflammatory response. Accordingly, with the use of the Drew technique, the attenuation of the systemic inflammatory response at the time of the expected peak levels has been shown to be comparable with the results achieved by using anti-inflammatory substances such as high-dose steroids [8].
The impact of our results on routine CABG procedures has to be further evaluated. We are currently investigating whether the Drew technique is a viable option in high-risk patients with compromised pulmonary function in whom continuous perfusion and ventilation of the lungs during surgery may reduce postoperative morbidity and mortality. It will also be important to compare the benefits of the Drew technique with minimally invasive techniques. In addition to maintaining lung perfusion, minimally invasive CABG is performed without an extracorporeal circuit, without, however, offering a blood- and motionless surgical field as does the Drew technique.
In conclusion, there is a considerable increase of cytokine levels in blood emerging from the pulmonary vascular bed during the early phase of pulmonary reperfusion after declamping of the aorta in CABG patients. In contrast, no such increase is found in patients operated with the Drew technique of bilateral extracorporeal circuits. In addition, retention of activated leukocytes and platelet–monocyte coaggregates is less in patients operated with the Drew technique. Two factors are deemed responsible for the observed effects. First, no artificial oxygenator with the intrinsic problem of contact activation is needed using the Drew technique. The patient's lungs function as oxygenators. Second, during cardiac ischemia, there is no reduction in pulmonary flow or oxygen delivery to the lungs. Accordingly, the pathophysiological changes of pulmonary reperfusion are prevented.
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Acknowledgments |
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Footnotes |
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Appendix A Conference discussion |
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TopAbstract1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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Dr Massoudy: No.
Dr von Segesser: And handling of patients with chronic obstructive pulmonary disease was no problem, the lungs coming over the heart and so on?
Dr Massoudy: You mean a surgical problem in the sense of the lungs intruded the surgical field?
Dr von Segesser: Yes.
Dr Massoudy: No, it wasn't. But I must say, we only had one patient with chronic obstructive lung disease in that group.
Dr von Segesser: In this one it was no problem?
Dr Massoudy: No. And in the others it wasn't also.
Dr J. Svennevig (Oslo, Norway): What do you think is the most important site of cytokine production during cardiopulmonary bypass?
Dr Massoudy: Well, the activation that occurs during passage of the lung is astonishing during reperfusion, so I think besides the oxygenator as the artificial blood gas surface which is used in the conventional technique, we have the problem of organ reperfusion. And this study is part of the investigation of the lung response, and obviously the lung response seems to be much more important in that sense as opposed to the heart, which we performed studies on before. And more important, the entire cardiac output has to pass the lungs, whereas only 5% of the cardiac output perfused the heart. So I think the lungs are very important in that sense.
Dr von Segesser: Is it lung ischemia or lack of metabolic function of the lung that brings up the problems?
Dr Massoudy: Well, it is hard to quantify the amount of bronchial artery flow. So I think it is mainly lung ischemia.
Dr V. Subramanian (New York, NY, USA): This is a very ingenious model you have presented, which may be extended to beating heart surgery because it will obviously provide a tremendous decompression of the right and the left heart to do complete revascularization, and I am not sure what the leukocyte response would be on that. Are you planning to extend the old Drew technique with beating heart and stabilization to achieve optimal condition for coronary artery anastomosis? We have been thinking about it for about a year since the introduction of a brief myocardial arrest with a combination of a cholinesterase inhibitor and beta blockade to have timed intervals of asystole. So I am very pleased to see that you have done your first phase of this study. Perhaps you ought to try to do this in a beating heart. It would be an ideal, interesting model.
Dr A.M. El Gamel (London, UK): The results that you have shown us today are quite interesting, but I am quite perplexed about the clinical implications of what you have done today, because the lung problems that we see postoperatively, if you are talking about ARDS, comprise a very small percentage. Most of the patients who go on bypass have release of cytokines. Why don't all of them have problems with their lungs? And that is the question that we need to answer. Although the cytokines are released, it doesn't mean that all these patients would be harmed by the release of cytokines. There are other mechanisms that protect the patients from the inflammatory cascade. And only a small proportion of the patients probably cannot cope with the inflammation, so how are you going to apply a procedure to every patient you operate on to catch the 1% that is going contract ARDS postoperatively, and have you got any thoughts on that?
Dr Massoudy: As I said, looking at the previous study, not only preliminary inflammatory response but lung function was also improved. And what I didn't show because it wasn't actually standardized, was that intubation time was shorter and stay in the intensive care unit was shorter. So these are factors that influence overall organization of the cardiothoracic department, I think, and actually can accelerate the patient's recovery.
Dr El Gamel: So how many patients normally in your practice have you been able to extubate early and how many you think with using this technique you will be able to reach? How big a percentage of improvement is in this technique routinely where it will have an impact on your work?
Dr Massoudy: Well, I think the technique is applicable to every patient, but standardized studies and randomized studies will have to show how much the improvement actually is.
Dr L. Parenzan (Bergamo, Italy): This paper took me back to the year when I read for the first time in the Lancet this Drew technique. You know, it was a very important paper because it was treating Down's syndrome, complete correction of Down's syndrome, the AV canal, in very small children. So this was pushing us to tell us of early repair of congenital heart disease. Now, I have been interested very much in trying to do cardiac surgery in the eastern part of Africa, actually in Nairobi, and I did find many problems, and the main problem is money; money in order to buy valves and oxygenators. Would you think it would be possible right now, in 1999, to use the Drew technique without an oxygenator in underdeveloped countries?
Dr Massoudy: Well, it is a technique without an oxygenator, so you could use it anywhere in the world without an oxygenator, and actually there are some papers which were published in the 1980s using a similar technique without an oxygenator, and at that time cost and money was actually a motive to investigate and put the method into practice.
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References |
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TopAbstract1. Introduction2. Subjects and methods3. Results4. DiscussionAppendix A Conference discussionReferences |
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) and Bilateral Circulation (•). Mean±SEM; between-group significance levels are placed above error bars.