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Ann Thorac Surg 2000;70:1451-1452
© 2000 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of North Carolina, Chapel Hill, North Carolina, USA
Address reprint requests to Dr Egan, Division of Cardiothoracic Surgery, University of North Carolina, CB 7065, 101 Manning Dr, Chapel Hill, NC 27599
Lung transplantation is a lifesaving therapy for selected patients with end-stage lung disease, but its application is severely constrained by a paucity of suitable donors. About 80% of donors have lungs that are deemed unsuitable for transplantation for a variety of reasons, including aspiration at the time of brain injury, neurogenic pulmonary edema, and adult respiratory distress syndrome developing as a consequence of other simultaneous injuries in patients who become multiple organ donors. Given that graft and patient 1-year survival rates for recipients of lung transplants are lower than those for any other transplanted solid organ, it is not surprising that lung transplant surgeons are often reluctant to implant lungs with less than favorable gas exchange characteristics. The shortage of lungs for transplant resulted in 485 deaths on the lung transplant waiting list in 1998 in the US [1], a number that has steadily increased since UNOS began tracking lung transplant data in 1989.
A potential solution for the lung donor shortage is the use of organs retrieved after circulatory arrest from so-called non-heart-beating donors (NHBDs) [2]. This approach has had limited success in other types of organ transplant [3, 4], but the lung may be an ideal organ for this strategy because, unlike other solid organs, the lung does not rely on perfusion for parenchymal cellular respiration to occur.
In this issue of The Annals, Takashima and colleagues from Okayama report their remarkable results of a simple experiment [5]. They employed a canine single lung transplant model that forces the recipient animal to survive solely on the function of the newly implanted left lung. This is a rigorous test because all of the cardiac output is directed to the newly transplanted vascular bed. Lungs for implant were retrieved from nonventilated nonheparinized dogs 3 hours after sacrifice by lethal injection of potassium chloride. Surprisingly, 2 of the control recipients survived a 6-hour observation period, solely on the function of a lung retrieved 3 hours after circulatory arrest. More surprisingly, administration of nitric oxide (NO) to a group of 6 recipients resulted in 100% survival to 6 hours with very acceptable gas exchange parameters from lungs retrieved from NHBDs 3 hours postmortem. However, what is truly amazing about this study was the observation that similar excel-lent gas exchange and pulmonary hemodynamics could be achieved in recipients of NHBD lungs even when NO was administered for only 1 hour after lung implantation.
We have been investigating the ischemia/reperfusion injury (IRI) of lungs retrieved from circulation arrested donors for several years. We have demonstrated that oxygen ventilation of circulation-arrested donors results in attenuation of lung cell death [6], maintenance of ultrastructure [7], and high-energy phosphate levels [8]. Employing an isolated perfused rat lung model, we have shown early alterations in filtration coefficient after circulatory arrest [9], attenuated by oxygen ventilation of the donor or by reperfusion with agents that increase cyclic AMP [10, 11].
Our experiments with isolated perfused lungs support the notion that the cyclic nucleotides cAMP and cGMP play an important role in stabilizing the integrity of endothelial barrier function during IRI (manuscript submitted). Although Takashima and colleagues did not measure cGMP in their transplanted lungs, it is likely that NO administration resulted in augmentation of this second messenger, because this is the putative mode of action of inhaled NO. Cyclic GMP is an intracellular second messenger that regulates three classes of effector proteins (cGMP-dependent protein kinases, cGMP-gated ion channel protein kinases, and phosphodiesterases) mediating protein phosphorylation, cation influx, and cyclic nucleotide catabolism [12].
Several investigators have documented the benefits of NO in models of lung IRI and lung preservation [13–15]. NO administration to donors at the time of harvest resulted in better lung function in recipients in a canine model [16]. In rat models of conventional lung transplant from circulation arrested donors, there is some controversy as to whether NO administration is more beneficial than stimulation of the NO pathway by administration of cGMP [17, 18]. In swine, NO administration to recipients of lung transplants results in reduced IRI [19]. Indeed, there is evidence that treatment of human recipients with NO after lung transplant is beneficial [20–22].
Bacha and colleagues used NO in NHBD swine lung transplant experiments [23]. NO was administered to both nonheparinized donors (for a 3-hour period of ventilated ischemia) and recipients. Survival and gas exchange were superior among the NO-treated animals. In a rat model of NHBD lung transplant, administration of NO to the donor and recipients resulted in better graft function [24]. In neither study were the results as dramatic as those reported by Takashima. However, there are almost certainly species differences in lung reperfusion injury. In addition, timing of NO administration may be important. In rats, administration of NO concomitant with the onset of reperfusion was deleterious, but delayed administration was beneficial in an in situ IRI model [25].
A fascinating conclusion of the work reported by Takashima and coworkers is that adequate pulmonary function may be achieved from lungs retrieved from NHBDs by manipulation of the recipient after the onset of reperfusion. That is, no manipulation of the donor was carried out at all, not even heparinization! There is growing evidence that lungs retrieved from NHBDs can provide adequate gas exchange function. Using a canine double lung transplant model, we have shown considerable increase in extravascular lung water with development of a substantial A-a gradient that improved over an 8-hour observation period [26]. Recently, we have used a rat lung transplant model to demonstrate acceptable gas exchange characteristics of lungs retrieved from NHBDs (manuscript submitted), while investigators in Sweden have shown excellent late gas exchange of rat lungs retrieved from NHBDs [27, 28].
There is no question that lung transplant is associated with transient dysfunction due to reperfusion injury, whether from a conventional brain dead, circulation intact donor, or from an NHBD. The burning issue before widespread clinical introduction of the use of NHBDs for lung transplant can be realized is: to what extent can the degree of IRI be predicted a priori and successfully treated in the recipient? The current report by Takashima and colleagues will become a classic paper precisely because it demonstrates that there are opportunities to minimize the impact of IRI in the setting of lung transplant from NHBDs. The challenge for Takashima and coworkers now is to determine why NO was so beneficial. What did administration of this agent for only a short time do to the pulmonary vasculature that allowed for excellent gas exchange in this model? Will the answer to this question make us confident to introduce the practice of lung transplantation from NHBDs in humans?
References
This article has been cited by other articles:
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  D. V. Raemdonck, W. Coosemans, W. Klepetko, J. H. Dark, S. Steen, and F. Rega Alternatives to lung donor shortage Surgery for Non-Neoplastic Disorders of the Chest: a Clinical Update, June 28, 2010; 89 - 112. [Abstract] [Fulltext] [PDF]
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 G. I. Snell, T. Oto, B. Levvey, R. McEgan, M. Mennan, T. Higuchi, L. Eriksson, T. J. Williams, and F. Rosenfeldt Evaluation of Techniques for Lung Transplantation Following Donation After Cardiac Death Ann. Thorac. Surg., June 1, 2006; 81(6): 2014 - 2019. [Abstract] [Full Text] [PDF]
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 T. Wittwer, U. F. W. Franke, A. Fehrenbach, M. Ochs, T. Sandhaus, N. Dreyer, J. Richter, and T. Wahlers Innovative pulmonary preservation of non-heart-beating donor grafts in experimental lung transplantation Eur J Cardiothorac Surg, July 1, 2004; 26(1): 144 - 150. [Abstract] [Full Text] [PDF]
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