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Ann Thorac Surg 1997;63:1390
© 1997 The Society of Thoracic Surgeons
DR JOHN C. WAIN (Boston, MA): Doctor Fujino and his colleagues are to be congratulated on an excellent study. My colleagues and I have actually used inhaled nitric oxide (NO) clinically in 4 donors for living-related lung transplantation. We have found excellent gas exchange in the recipients of these grafts, as you have in this experimental model. Fortunately, we have not had the opportunity to look at the gross histology of those lung grafts late postoperatively. I was wondering if you had noticed any histologic differences in the lungs in these canine models at the time of sacrifice, the ones that received NO versus the ones that did not receive NO?
DR FUJINO: Sorry, we did not make histologic assessment of these grafts.
DR G. ALEXANDER PATTERSON (St. Louis, MO): Doctor Wain, can I ask you how you measured the effect of inhaled NO in those living-related transplants?
DR WAIN: Well, there is no way for us to really be sure that NO administration was beneficial. However, the lung grafts worked exceedingly well in terms of gas exchange. Although they all had short ischemic times, averaging 65 minutes, after implantation the pulmonary venous oxygen tension from the grafts averaged about 475 mm Hg, which is significantly better than the graft gas exchange we have seen with any cadaveric transplantation. There was no evidence of methemoglobinemia in the donors or recipients, and intraoperative biopsy of the grafts within 30 minutes of reperfusion showed no acute changes. We have also not seen any late parenchymal or airway changes in these grafts, as assessed by transbronchial biopsy, that we might ascribe to the use of NO. However, as I say, it is very difficult for us to ascribe a benefit to the use of donor NO in these cases. This excellent experimental study provides good validity for such an approach, but the concerns about NO administration and its potential toxic effects either directly or by the generation of hydrogen ion-containing radicals still persists, which is why I was curious about any histologic findings in this model that might sway us one way or the other.
DR BERNARD A. HAUSEN (Menlo Park, CA): I enjoyed the paper as much as I enjoy all the work that comes from your laboratory.
I have a question regarding the inhalative use of NO: in a lot of donors we use for lung transplantation we see atelectasis and find significant amounts of secretions. In many of those lungs, the NO will not go to some areas that have atelectasis and secretions. These areas will then be hypoperfused. That means that the preservation solution will go only to the area that is best ventilated. This may be desirable during reperfusion, as it reduces the ventilation/perfusion mismatch, but in organ preservation it is something we do not want because we actually want every cell in the lung to receive the preservation solution.
DR PATTERSON: That is an excellent question. These were normal canine lungs. A valid criticism of most reperfusion injury studies is that the lungs used were normal at the start of the experiment. It would be interesting to know whether or not one would observe the same effects if a local atelectasis or some sort of donor lung injury were created before harvest.
DR HAUSEN: I have just published exactly the same experiment in the December issue of Transplantation, and I have done it in the double-lung transplant model of rats. My results, unfortunately, were almost opposite to yours. That is, I guess, the way science is. I saw very, very poor function after donor NO treatment, and I attributed it to areas of atelectasis that I probably was not able to see during hyperinflation, as well as some secretions. The lungs were not homogeneously perfused. That was my explanation. Now, you are also using normal, healthy animals and you get the opposite results. Maybe that is species-dependent or because my dose was 20 ppm and you went up very much higher.
Regarding the high dose, I was a little concerned. I discontinued NO administration, then inflated the graft with 100% oxygen to avoid the possibility of development of oxygen radicals through NO, which is known to happen, especially at that high concentration. Were you not worried about that?
DR PATTERSON: We cannot answer the question. We know that a more or less maximal effect was observed at 60 ppm. We have observed clinical improvement in patients with lung injury at that level. That is the level we chose to administer before harvest in these experiments.
DR HANI SHENNIB (Montreal, Que, Canada): Your control arm was one that received NO before harvest. If you look at the myeloperoxidase level and the other parameters that you measured, there is what you see as a statistically significant difference, but biologically it is not that impressive, the groups are really pretty close to each other. Do you have any data from other controls, perhaps, in the laboratory to show that there is definitely a significant improvement over the animals that received NO?
Your control group here has already received NO before harvest. Do you have any data from your laboratory to show that in animals that did not receive NO, even at the time of harvest, there is damage that is statistically significant, and biologically significant, compared with the arm that you have here in which NO was given after transplantation and showed improvement in all the parameters that you have shown here today?
DR PATTERSON: In this experiment there was a group of animals that received no NO at any time and there was another group of animals that received NO only at the time of harvest. No animals received NO after the reperfusion or during the reperfusion. The myeloperoxidase data and the wet/dry weight ratio data for the control group, in other words, the no treatment arm, are similar to those in other control groups in our previous experiments using the same model.
DR HIROSHI DATE (Okayama, Japan): I congratulate you for accomplishing a very nice study. Because we know that NO has very short half-life, which occurs by the rapid metabolization by hemoglobin, it is very hard to understand why NO is effective during the extended preservation period. Is that because you flush out all the blood from the donor, and does NO remain in the donor lung for an extended period of time?
DR PATTERSON: I think that is the reason. We did not; however, measure alveolar NO concentrations at the end of the preservation period. In these healthy donor dogs receiving NO inhalation, the effluent at the end of the flush is clear, presumably because there is very little blood, if any, in the pulmonary circulation. It is possible that the NO is not inactivated during the period of storage.
Related Article
Ann. Thorac. Surg. 1997 63: 1383-1389.
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