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Ann Thorac Surg 1995;60:44-46
© 1995 The Society of Thoracic Surgeons
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Introduction |
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 Top Introduction |
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DR THOMAS M. EGAN (Chapel Hill, NC): I am not sure that your data have excluded the possibility of 30 minutes of warm ischemia, and I still do not think that you or we have established a time window for which this approach may be practical.
I have a couple of other points. Did you look at the airway anastomoses? We have had a lot of problems performing survival lung transplantations in pigs with airway strictures, and at least in our hands it is a tougher model than the canine model and certainly tougher than it is in humans to get a good airway result. Could your problems with compliance be a reflection of an airway problem?
The second question relates more broadly to the issue of what is allowable and what is recoverable. Do you know what happens to airway dynamic compliance in humans after lung transplantation, and have you done any measurements in your transplant patients? Is the degree of compliance difficulty that you have had compatible with a successful outcome after human lung transplantation?
DR BUCHANAN: Regarding the first question, we did have to exclude 2 animals because of narrowing at the anastomotic site. We thought that these were technical complications; however, there is always a risk that ischemia to the airway itself can present as narrowing after it has undergone some healing. Therefore, I am not sure that we have completely answered that question either. In each study animal, we did rule out narrowing at the bronchial anastomosis before recording the data using a bronchoscope. Regarding our dynamic airway compliance numbers, I do not believe narrowing at the bronchus was a factor.
Regarding this drop in compliance, we have certainly seen very stiff lungs develop in patients after lung transplantation, but they do seem to get through this. And so the question is: How bad can the drop in compliance be before it becomes irreversible? We have not answered that question fully, and I think more studies are indicated.
DR RICHARD J. NOVICK (London, Ontario, Canada): First, concerning the airway issue, have you measured bursting pressure or any other index of airway healing to determine at 7 days whether 30 minutes of warm ischemia of the airway is deleterious? Second, before the confounding variables of rejection and immunosuppression come into play, a series of measurements taken immediately after the transplantation with the right hilum clamped would have been illuminating.
DR BUCHANAN: We did not do any bursting pressure measurements in our model. We did simply look at the airway anastomosis histologically. We considered recording airway dynamic and hemodynamic data at the time of implantation, but we believed that the additional dissection and clamp-related trauma would prohibitively increase the operative risk.
DR LARRY R. KAISER (Philadelphia, PA): I congratulate you, Dr Buchanan, on an excellent presentation, and I thank the investigators, who provided me with a copy of their manuscript before the presentation.
You have extended the work that Tom Egan has done, and I think we are getting close to perhaps considering this clinically. I wonder what you would do with a situation if you walked into a harvest and the heart had just fibrillated 2 or 3 minutes before, would you take those lungs based on your current evidence? What are your future studies? Do you plan to extend the limits beyond 30 minutes perhaps, because it seems that dynamic airway compliance was the only thing that really changed, and perhaps we can extend it. I think that with the logistics that one has to face clinically, if it is perhaps a little longer than 30 minutes, we may be able to really extend the number of donors that potentially will be useful to us.
DR BUCHANAN: Doctor Kaiser, thank you for reviewing the article. Yes, I definitely would be very interested in harvesting lungs from the fibrillating patient you described. I believe our data would support the notion that such lungs could be expected to function very well.
Regarding future studies, we do have plans to extend the period of in situ warm ischemia beyond 30 minutes. Hopefully, the outer limit of tolerable warm ischemia for lung transplantation can be delineated.
DR FRANCIS ROBICSEK (Charlotte, NC): This is a very interesting experiment, and I believe that it may very well have practical clinical significance.
I would like to call your attention to some of the work we had done when we removed the heart and lungs ``en bloc'' from recently deceased humans, and after 30 to 45 minutes of ischemia resuscitated the heart using a heart–lung machine and converted it into an autoperfusing heart–lung preparation. Both the heart and the lungs functioned quite satisfactorily thereafter. Although the organs were not transplanted at that time, these experiments, which were published in 1969, have proved that the heart and the lung removed from the human cadaver can be resuscitated and can function satisfactorily.
DR BUCHANAN: Doctor Robicsek, thank you for your comments. Your seminal contributions clearly laid the foundation for the work we are doing now.
DR ROBERT M. MENTZER, JR (Madison, WI): I compliment you on your fine presentation and for sharing this important information with us. I would just like to bring to your attention that the University of Wisconsin has been very active in using non–heart-beating donors as a source of extrarenal organs. In fact, our transplant program has been able to increase the number of organs transplanted by 8.6% over a 17-month period. About a year ago, Dr Robert Love from our institution performed a lung transplant operation using a non–heart-beating donor with a 30-minute ischemia time. He is going to discuss this at the upcoming heart and lung transplant meeting in San Francisco. Your experimental data support our experience in the clinical setting.
The other aspect that I would emphasize, however, is that many of the problems associated with using non–heart-beating donors have more to do with social and ethical issues yet to be resolved. Finally, in the setting of limited organ availability, utilization of a donor organ has to be balanced with the urgency of need of the recipient.
DR BUCHANAN: Doctor Mentzer, I will look forward to hearing Dr Love's presentation. I agree that ethical and social issues will dominate any upcoming debate about non–heart-beating organ donation. If and when we proceed on a routine basis with non–heart-beating organ harvests, these issues will need to be addressed carefully to avoid damaging the credibility of organ donation in general.
DR PAULO F. G. CARDOSO (Porto Alegre, Brazil): We also have been looking at the issue of postmortem lung viability in an experimental setting, using the same animal model proposed by Dr Egan. We looked at the effects of prostaglandin E1 in canine lungs submitted to 3 hours of warm ischemia in situ. We found that this is the time limit to which canine lungs can tolerate the ischemic injury and remain viable, and this is in accordance to the findings of Dr Kayano from Japan. We have also observed that large doses of prostaglandin E1 added to the flush solution delivered to the lungs, result in a slightly better posttransplantation function of the lungs. I have not heard you mention the use of a vasodilator in your presentation. Therefore, my question is whether you used prostaglandin E1 or not.
DR BUCHANAN: When we flushed our lungs, we used unmodified Euro-Collins. We did not add steroids. Prostaglandin E1 can be helpful in lung transplantation because of vasodilatation and more uniform distribution of flush. In addition, there certainly could be an antiinflammatory effect that might play a particularly important role in the non–heart-beating donor setting. However, we did not use prostaglandin E1 in this model.
DR THOMAS R. J. TODD (Toronto, Ontario, Canada): I would like to make two comments. First, to augment what Dr Egan said, I would not be too fussed about the difference between 15 and 30 minutes. In our laboratory we have been able to show in acute transplantation and in ex vivo measurements that Dr Egan's times of 4 hours are probably close to being accurate in terms of preservation of acute lung function. And in terms of the dynamic compliance that you are concerned about, that, too, would not worry me a great deal. We know from the adult respiratory distress syndrome literature that patients who have been ventilated for long periods of time in the intensive care unit with adult respiratory distress syndrome show continued improvement in their lung compliance up to and including 12 months after their discharge from the intensive care unit and the removal of ventilatory support. And we have certainly shown that even in the presence of very significant fibrosis, including intraalveolar fibrosis in some of our early transplants in Toronto, that the return to absolutely normal lung compliance in single lung transplants occurred several months later.
Finally, someone asked whether you would take a heart that was fibrillating as you were getting ready to take the graft; I sure would hope so. I would remind you that when we first started doing transplants in Toronto we did not flush, we did not use prostaglandin E1. We took it out and just submersed it in cold Euro-Collins solution; therefore, I do not think there is any question that if the heart is fibrillating, you should take it.
DR MALCOLM M. DECAMP (Boston, MA): You picked 7 days to look at the outcome variables, and a lot of the ischemia reperfusion events may happen a little earlier. Ischemia reperfusion may also set you up for earlier rejection and more problems with rejection. Do you have any plans to use the model to look at some intermediate time points, maybe longer than the 8 hours but before 7 days, and any other insights that you might give us into some of the in-between variables that might be important?
DR BUCHANAN: Clearly, the ideal study would be designed to characterize not only the severity of lung dysfunction after non–heart-beating organ donation, but also the time course of its occurrence. One could take functional measurements immediately after implantation which could then be repeated on days 3, 7, 10, 15, and so on until lung function stabilized. I suspect such a study would need to be carried out for at least several months. Our current technique involves sacrificing the recipient to obtain a complete set of measurements, obviously preventing such a longitudinal approach.
DR JOSEPH E. BAVARIA (Philadelphia, PA): I enjoyed your paper very much.
I noticed at the end you provided a 'caution' about a controlled environment because of the 15- to 30-minute window. The question I have for you is: Have you performed any pretreatment studies to extend that window by, say, giving the donor inhaled nitrous oxide or steroid administration beforehand or any calcium channel blockers or any ischemic reperfusion modulators?
DR BUCHANAN: I think that is fruitful ground. Perhaps Dr Egan could answer that question better than I. He has published an article using free radical inhibitor in the non–heart-beating donor setting and in fact, has shown some improvement. But I think that there are many things we could do. For example, we could treat the drop in compliance by administering exogenous surfactant, either at the time of implantation or when the fall in compliance is noted in the intensive care unit.
DR EGAN: Just to comment on the whole notion and some of the work that we have done with free radical scavengers, it is clear that we do not know the tolerable limit to ventilated ischemia of the lung. The thing that is unique about the lung is that it is the only solid organ that does not rely on vascular perfusion for cellular respiration. If you think about it, parenchymal cells in the lung ventilate across a gas phase, and perfusion is solely for providing substrate, that is, glucose, and washing out metabolic by-products, therefore, the lung may have a very large window of tolerance for normothermic ischemia. It is along the lines of that notion that we have started to look into this as a source of donors. And, frankly, we would evaluate today potential donors whose family wants life support withdrawn but who do not meet criteria for brain death. If those lungs function well from a gas exchange point of view and if the bronch is clean, then we would harvest those lungs after cardiac arrest, assuming we had family consent.
DR YUJI SHIRAISHI (Los Angeles, CA): As you know, in Japan brain death is not accepted, so your results encourage Japanese thoracic surgeons to go to clinical transplantation.
I have one question. Do you have any model to induce cardiac arrest by increasing intracranial pressure?
DR BUCHANAN: There is a group in Japan led by Dr Shimada who has done a non–heart-beating donor lung experiment, published in Transplantation Proceedings in the last year, in which he and co-workers induced significant brain injury by inflating a Foley catheter in the brain in their donors before withdrawing support. They reported excellent results.
DR SHIRAISHI: Did you measure any hemodynamic parameters between asphyxiation and cardiac arrest?
DR BUCHANAN: No, sir, we did not.
DR SHAF KESHAVJEE (Toronto, Ontario, Canada): My comment is directed particularly toward the statements that have been made regarding translation to the clinical setting. You describe a model where you have a stable donor and a period of in situ warm ischemia followed by harvesting. What has not been taken into account is what happens to a donor before that event. We have just completed a series of experiments that showed that although after death in a nonheparinized, nonventilated animal model, lungs can be used after a period of 3 hours of warm in situ ischemia, if those same lungs are exposed to 1 hour of significant hypotension before death, those lungs are completely ruined and nonusable. Therefore, I think before we translate to the clinical setting we have to realize that all non–heart-beating donors are not the same and the effects of what happened to them before death may have an impact on subsequent function.
DR BUCHANAN: It may well be that the stable non–heart-beating donor is a very rare phenomenon. We need to take your comments into consideration, both in planning future experimental studies and in carrying out clinical lung harvests.
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