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Eur J Cardiothorac Surg 2007;31:462-467. doi:10.1016/j.ejcts.2006.11.050
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Division of Thoracic and Cardiovascular Surgery, Heart Center Leipzig of the University of Leipzig, Struempell Str. 39, 04289 Leipzig, Germany
Received 5 September 2006; received in revised form 17 November 2006; accepted 28 November 2006.
* Corresponding author. Tel.: +49 341 865 1422; fax: +49 341 865 1452. (Email: hartmuth.bittner{at}medizin.uni-leipzig.de).
| Abstract |
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Key Words: Lung transplantation Extracorporeal support techniques Cardiopulmonary bypass Extracorporeal membrane oxygenation Intra-operative ECMO
| 1. Introduction |
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The use of CPB, however, can lead to early graft dysfunction and bleeding-associated complications due to the required full systemic heparin administration and the activation of inflammatory mediators [5,6]. Extracorporeal membrane oxygenation (ECMO) support is an alternative technique of extracorporeal circulation, which has already been used during the initial stage of lung transplantation [7]. ECMO has the capacity to support gas exchange and hemodynamics without the need for high-dose heparin administration and anticoagulation therapy. Its prolonged use and positive impact on outcomes following graft failure after lung transplantation is well documented [8].
This study was designed to investigate the efficacy and safety of the intra-operative use of ECMO in patients undergoing lung transplantation surgery for various end-stage lung diseases compared with standard CPB support techniques.
| 2. Patients and methods |
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2.1 Extracorporeal circulatory support devices
The ECMO heparin-bonded circuit used was the D905 EOS ECMO hollow fiber membrane oxygenator (COBE, Cardiovascular, Anvada, CO, USA), 1.2 m2 membrane surface area, priming volume 300 ml, and heat exchange surface area 0.14 m2 allowing maximal blood flow of 5000 ml/min through heparin-bonded tubing and cannula system.
The CPB system used was the MEDOS HLITE 7000 heart-lung machine series (MEDOS, Stolberg, Germany) in combination with Stöckert's third-generation perfusion system consisting of a hardshell venous reservoir (4000 ml), heparin-coated hollow fiber oxygenator (surface area 1.9 m2), heat exchanger (0.45 m2), priming volume 1200 ml, and cardiotomy section allowing blood flow rates of 17 l/min. The Medtronic Carmeda heparin-bonded tubing circuit (Medtronic Cardiopulmonary, Anaheim, CA) was used for both circulatory support systems. Heparin infusion was titrated to maintain an activated clotting time (ACT) of >450 s for CPB supported lung transplant operations and 160220 s for the ECMO supported procedures. CPB and ECMO flows were 2.0 to 2.4 l/min/m2. Packed red blood cell (PRBC) transfusion was performed when the hematocrit dropped below 30%. Normothermia was maintained in all patients.
2.2 Donor and recipient surgery
We used well-established criteria for accepting donor lungs including objective evidence of adequate gas exchange and bronchoscopic evaluation to exclude aspiration or purulent secretions [9]. Standardized organ procurement and recipient implantation techniques were utilized for lung transplantation (cold crystalloid preservation solution of low-potassium dextran solution or LPD, Vitrolife, Gottenberg, Sweden) was infused via the donor pulmonary artery at low pressure in an antegrade fashion immediately following prostaglandine intrapulmonary artery injection. During the procurement, the vascular structures were divided in situ and the trachea dissected well proximal to the carina. With the lungs partially inflated, the trachea was divided between staple lines and the organ transported to the center was immersed in LPD.
A pulmonary artery catheter was inserted through the right neck to monitor continuously the right arterial and pulmonary artery pressure and a double-lumen endo-tracheal tube was placed allowing isolated lung ventilation. Double lung transplantation was performed using a sequential single lung implantation technique either through bilateral anterolateral thoracotomies without transverse incision of the sternum. Rarely, bilateral posterolateral thoracotomies were indicated for sequential single lung transplantation when mediastinal shifting led to difficult exposure of lung hilum structures requiring turning and re-draping the patient (one patient). Single lung transplantation was performed through a serratus muscle-sparing posterolateral thoracotomy.
Once the donor lung was present in the operating room, the recipient pneumonectomy was completed. The bronchial anastomosis was accomplished first and was generally followed by the vascular pulmonary artery and left atrial cuff anastomoses. De-airing was done thoroughly through the atrial cuff anastomosis.
In all patients of this study, ECMO and CPB support was set up through the femoral veno-arterial vessels. Monofilament 5-0 purse string sutures were applied to the anterior wall of the femoral artery and vein. The Seldinger canulation technique was used to introduce minimal-invasive cardiac surgery heparin-bonded venous (usually 22 Fr) and arterial cannulas (18 Fr). In case of small arterial diameter and complete occlusion of the vessel by the arterial cannula, a separate arterial cannulation (10 Fr) of the distal limb was performed.
2.3 Data analysis
Statistical analysis was conducted using analysis of variance (ANOVA) and followed by unpaired Student's t-test to determine significant differences between groups. Categorical data were analyzed by chi-square tests. The association between risk factors and mortality was first analyzed with Fisher's exact test. A logistic multivariate regression model was then used to examine synergistic effects of potential predictors (massive blood product trasnsfusions of greater than 8 units of packed red blood cells, ECMO use, CPB use, survival). The statistical analysis was performed using SPSS 12.0 and Microsoft Excel. Results are expressed as means ± the standard errors. Significant differences are reported as exact p-values.
| 3. Results |
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Using the ISHLT lung transplant injury grade III, defined by a FiO2/PaO2 ratio of less than 200 mmHg was measured within the initial 48 h after transplantation, led to the identification of one patient in the CPB group and one patient in the ECMO group with severe post-transplant ischemiareperfusion injury. Following bronchoscopy, chest-X-ray, and chest computed tomography examinations the patients were taken back to the operating room. The previously ECMO-supported patient improved following evacuation of large chest cavity hematomas, which compromised transplant lung inflation and expansion. A thorough inspection did not reveal surgical bleeding sites. The CPB supported patient (idiopathic fibrosis, secondary pulmonary hypertension, systolic pulmonary artery pressure 90 mmHg, right heart dysfunction) with severe ischemiareperfusion injury developed graft failure and required immediate ECMO support and massive blood product transfusions. This patient died on post-operative day 10 due to therapy-resistant coagulopathy, right heart failure, and intracranial bleeding. In this patient several re-explorations and thoracotomies for bleeding were performed; however, an obvious surgical bleeding site was never identified.
The requirement for blood product administration (packed red blood cell) was significantly different between both groups during the operation and over the first 72 h. Their average transfusion requirements were 13.25 ± 1.6 PRBC units in the ECMO supported patients versus 5.7 ± 2.8 PRBC units in the CPB-supported lung transplantation patients (p = 0.02). For comparison, the patients undergoing lung transplantation without extracorporeal support required 2.7 ± 0.9 PRBC units over the first 72 h (p < 0.001). Multivariate regression analysis revealed that eight and more PRBC units transfused within the early post-operative period reached near significance for mortality prediction in combination with the use of ECMO (p = 0.06, 95% confidence interval 9.5716.93).
Three of the ECMO and one additional patient of the CPB-supported group died within 90 days of the lung transplantation procedure due to infectious complications. Three patients developed severe CMV and HSV viral sepsis (all recipients were CMV Ig-positive and one donor was CMV Ig-positive) and one patient expired of lung transplant bacterial pneumonia (Klebsiella pneumoniae, Pseudomonas cultured) induced graft failure and intracranial hemorrhage under delayed ECMO support. The 1-year survival rate was reduced (p = 0.004, log-rank test) in the ECMO-supported patients. Table 1 summarizes the important findings.
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| 4. Discussion |
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The use of extracorporeal membrane oxygenation became a last resort treatment option for lung transplantation patients after surgery who developed severe ischemiareperfusion injury and graft failure following surgery [8]. Many lung transplant centers judged the elective employment of ECMO as justified if graft failure is related to the ischemiareperfusion syndrome, which is associated with hypoxia, endothelial permeability increase, and dense pulmonary infiltrates formation [17]. Only limited reports exist, which describe the intra-operative use of ECMO for lung transplantation surgery. Ko et al. described their experience of intra-operative ECMO use in five patients with primary pulmonary hypertension. ECMO support was extended into the post-operative period. All lung transplant patients had an uneventful recovery with excellent graft function [18]. Bilateral lung transplantation with intra- and postoperatively prolonged ECMO support was used in 17 patients with primary pulmonary hypertension [4]. Controlled reperfusion prevented the occurrence of reperfusion injury when ECMO was extended into the ICU treatment interval. However, rethoracotomy for bleeding was required in 25% of the total ECMO population, although heparin-coated tubing sets were used and systemic administration of heparin was avoided. Of note, they report only two deaths despite the use of ECMO. Ko et al. [19] extended their experience of intra- and post-operative ECMO support to 10 single and 3 bilateral sequential lung transplantations for various causes of end-stage lung diseases. It was concluded that ECMO rather than CPB should be used for lung transplantation surgery. Multiple blood transfusions were required for bleeding and to maintain the hematocrit above 30% (intra-operative 230 units, post-operative 09 units of packed red blood cells), which was comparable to the results of the present study.
In this study, the surgical approach was identical in the ECMO and CPB patients. In all patients a limited access muscle- and sternum-sparing thoracotomy were performed and thoracoscopic instruments used. The femoral arteries and veins were cannulated for both techniques utilizing cannulas as frequently used in minimal invasive heart valve surgery. This provides an undisturbed and unobstructed surgical field at the lung hilum structures. Both support techniques maintained a high level of oxygenation and oxygen saturation throughout the operations. However, CPB achieved better hemodynamic support, allowed greater flow rates, and was independent of frequent fluid supplementation. One major advantage was the implementation of cardiotomy suction in all CPB-supported procedures, which allows the immediate return of the lost fully heparinized chest cavity blood and the establishment of a blood-less field. The results of this study show that high-dose heparinization was not associated with increased blood loss in CPB-supported lung transplantation operations. The major advantages of CPB support became obvious when very adipose patients and patients with large BSA presented with narrow chest cavities (as it is in idiopathic pulmonary fibrosis) and right heart hypertrophy and dilatation (patients with primary or secondary pulmonary hypertension). In these patients the lung hilum structure exposition for precise lung transplantation surgery required aggressive heart manipulations, pushing, lifting, and shifting. This was readily achieved in the CPB supported operations due to stable and higher CPB flow rates and maximum venous drainage capabilities leading to an empty-beating heart status with improved intrathoracic views. If there is need for extension of extracorporeal circulatory support into the post-operative period in CPB supported operations, the ECMO circuit could be connected to the already inserted femoral vessel cannulas with ease.
| 5. Limitations of the study |
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In summary, extracorporeal circulatory support is required in certain lung transplantation operations. The ECMO supported lung transplant procedures required significantly more blood transfusions. The negative effects of multiple blood transfusions in the ECMO patients might have contributed to the extended ventilatory times, infectious complications, and mortality rates compared with the CPB supported lung transplantation operations. CPB remains the standard of support technique if extracorporeal circulatory support is indicated for lung transplantation surgery.
| Appendix A |
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Dr R.D. Davis (Durham, North Carolina, USA): I assume you were doing VA-ECMO for all these patients; is that correct?
Dr Bittner: That's correct.
Dr Davis: Have you ever tried using VV-ECMO as a support in the patients who really dont need hemodynamic support but rather oxygenation? We had excellent luck with doing that and it makes the anesthesia much easier and you can actually achieve the same thing without the femoral arterial complications that you tend to get as well as the systemic embolic phenomena.
And my other question that gets into this is the difference between your cardiopulmonary bypass group and your ECMO group in terms of blood utilization. Were you using some sort of scavenger circuit? And can you try to explain why you felt like you ended up with what appeared to be a much worse coagulopathy with the ECMO. It seems like you probably had a lot of blood loss and that you ended up giving defibrinated blood back in terms of using your BRAT circuit or whatever youre using.
Dr Bittner: For the first question, yes, we have also tried and still use VV-ECMO support, but primarily in patients which present following the operation with graft failure which cannot be treated by less aggressive methods (turning the patient and frequent position changing, prone positioning). And the VV-ECMO can easily be performed in the intensive care unit, without going back to the operating room, with quite a success.
However, the VV-ECMO support does not support the hemodynamics, and some of these patients required intraoperatively additional hemodynamic support, which is often not sufficiently achieved through catecholamine administration. Subsequently, for additional hemodynamic support, I think, I believe, that VA ECMO support is necessary allowing you very higher flow rates.
Now, compare that to the cardiopulmonary bypass procedures and here is the answer to your second question in order to run ECMO efficiently in these patients who present, due to their end-stage lung disease majorly dehydrated, they require efficient flow rates of 4 l/min when hemodynamic instability occurs associated with a lot of volume administration. We hesitate to give crystalloids due to the capillary leak phenomena. We give blood liberally to allow for efficient ECMO runs. That is one of the reasons why the ECMO patients had more blood transfusions and a higher requirement of FFPs compared to the cardiopulmonary bypass group. Furthermore, the priming volume is 1200 ml, which also helps to run cardiopulmonary bypass efficiently because they get right away 1.2 l to support flow.
The use of the cardiotomy suction devices in the cardiopulmonary bypass group allowed the immediate return of chest cavity collected blood. In addition, the limited access lung transplant procedures can also lead to more fluid requirements due to the insignificantly longer operation times and the limited venous drainage and heart emptying in the ECMO patients. This can lead to difficult lung hilum exposure and frequent instability due to heart lifting and heart manipulations.
Dr W. Klepetko (Vienna, Austria): As you might have realized, your work is a bit opposite to what is our philosophy and what we reported yesterday. Now, the over all experience with ECMO cases you are presenting here is 10 or 11 patients. What we have seen in our series was a certain learning curve. Therefore, might it be due that there is as well a pronounced learning effect especially in the limited number of your patients.
Another question I would also like to raise is in regard to the blood loss you reported. Does this include intraoperative blood loss only or is the immediate postoperative period included?
Finally, we have identified the combination of induction therapy with ATG and the ECMO use as a problem especially for the function of the thrombocytes. Have you done the same observation?
Dr Bittner: To your first question in regards of learning curve, yes, since we just established our lung transplant program, there is an institutional learning curve which I cannot deny. I cannot compare the presentation of the data here to your great presentation of intra-operative ECMO use of your group yesterday because your study is a retrospective analysis, no comparison to CPB made, and the mix of patients you presented yesterday is not so prominent.
The third question was the immunosuppression and ATG in association with bleeding problems. As I stated, all patients had the same very aggressive immunosuppression protocol consisting of glucocorticoids, CNI, and CellCept.
| Footnotes |
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| References |
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This article has been cited by other articles:
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P. Korvenoja, O. Pitkanen, E. Berg, and L. Berg Veno-venous extracorporeal membrane oxygenation in surgery for bronchial repair. Ann. Thorac. Surg., October 1, 2008; 86(4): 1348 - 1349. [Abstract] [Full Text] [PDF] |
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