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Ann Thorac Surg 1996;61:1123-1124
© 1996 The Society of Thoracic Surgeons
DR CURTIS G. TRIBBLE (Charlottesville, VA): This is a very interesting report, and it addresses a problem that many of us have faced over the years. It will certainly add to our armamentarium for dealing with patients with pulmonary hypertension or the need for two ventricular assist devices instead of one in settings of pulmonary hypertension. Perhaps this technique may even be useful in the setting of the lung transplantation with pulmonary hypertension.
We, at the University of Virginia, under the generation-long tutelage of the physiologist Dr Robert Berne, have a long devotion to adenosine. We have been taught to call it the ``Queen Metabolite.'' It seems like it affects almost every physiologic process in some positive way. We have looked at it in cardioplegia, in spinal cord protection, and in an effort to protect platelets during cardiopulmonary bypass. One of the things that we have learned is that adenosine has the beauty of being very short-acting, having a very short half-life. We also learned, however, that one of the potential disadvantages of adenosine infusions is that its metabolites are not nearly so short-lived and that these metabolites may be harmful.
So the questions that I would like to bring up are whether or not you had any opportunity to measure some of these metabolites-inosine, hypoxanthine, and xanthine-whether or not you have developed any feel for how long this adenosine infusion can be maintained, and whether or not these metabolites might cause harm in the long run. As everyone knows, attempts have been made to block the subsequent metabolism of inosine to xanthine and hypoxanthine with allopurinol, leading me to ask whether or not the addition of allopurinol should be part of the overall treatment to allow us to use adenosine this way.
DR FULLERTON:Thank you, Dr Tribble. In answer to your first question, we, unfortunately, currently lack the ability to measure these metabolites. Although what you say is quite accurate, we have been unable to pursue that. Once we have the ability to measure that, that would be a very interesting thing to do.
Although these metabolites had the potential to impede cardiac function, in part in answer to your second question, the longest duration of infusion that we have used is approximately 4 days, and that was in a patient with severe refractory pulmonary hypertension in whom all other modes of pulmonary vasorelaxation failed. That patient experienced no decline in cardiac output. In fact, on a daily basis that patient demonstrated a marked improvement in cardiac function. Acknowledging that that is a crude measure of contractility, we have not seen any detriment to its use.
I think the suggestion for the use of allopurinol is superb. We have not used that. However, that would offer the advantage of lowering the dose of adenosine that is being used and potentially avoiding some of these unwanted side effects.
DR CONSTANTINE MAVROUDIS (Chicago, IL): I enjoyed your presentation very much. We performed a similar series of experiments in infants with atrioventricular canal and pulmonary hypertension using inhaled nitric oxide as a pulmonary vasodilator. We found, of course, that an accurate repair was instrumental in lowering the pulmonary artery pressure significantly and that subsequent inhaled nitric oxide administration lowered the pulmonary artery pressure only slightly more. It appears that your experiments went well too, because your postoperative pulmonary artery pressure was only 37 mm Hg and was lowered to 25 mm Hg after therapy. It is unfortunate for your experiments, and ours, that the pulmonary artery pressure was not higher to give a true test of drug vasodilatory capability. I am curious as to why you did not include inhaled nitric oxide therapy as an additional therapeutic arm in your experiments.
DR FULLERTON:Thank you for your comments, Dr Mavroudis. To answer your second question first, we also use nitric oxide, and it probably has evolved into a first line of defense in the treatment of pulmonary hypertension. What we have found in our experience, as well as in the experiences of others, is that approximately a third of patients treated with inhaled nitric oxide failed to respond to it. The reasons for this are somewhat unclear, but in series in which inhaled nitric oxide has been used in the treatment of adult respiratory distress syndrome or after either adult or congenital heart operations, about a third of patients fail to respond to it.
Now, this is particularly vexing in situations in which pulmonary hypertension must be controlled, and therefore I think it is important to continue to pursue other avenues. Along these lines, in our own series that is yet to be reported, the third of patients who failed to respond to nitric oxide do respond to adenosine. I think it probably has something to do with the fact that nitric oxide works through a cyclic guanosine monophosphate–mediated pathway, whereas adenosine works through a cyclic adenosine monophosphate–mediated pathway. I suspect that these two different mechanisms of signal transduction therefore are differentially affected under various forms of acute lung injury or chronic lung injury. So I think that although I would be loath to advocate the use of adenosine as the initial treatment of pulmonary hypertension, I do think it is another arrow that one can have in one's quiver for the treatment of pulmonary hypertension, particularly in situations in which other agents fail to work.
DR TODD L. DEMMY (Columbia, MO): I did a series of experiments and found that adenosine also improved cardiac function after ischemia because of its effect repleting high-energy phosphates. I have two questions: The first is, how did you control for the possible improvement in cardiac function due to the adenosine? And the other is: How did you arrive at the dose? I found that prolonged cardiopulmonary bypass accelerated the metabolism of adenosine. Did you find as time passed after cardiopulmonary bypass that your dosage requirements were reduced?
DR FULLERTON:We chose the dose based on data published in the British Journal of Pharmacology, in which dose-response curves to adenosine were generated in humans. This appeared to be a dose at which minimal systemic effects were observed. It is true that if you double this dose, it will spill over into the systemic circulation and significant hypotension will occur. It has been used effectively for controlled hypotension during neurosurgical procedures, for instance. This is the only dose that we have used in such a protocol, so I really cannot answer your second question.
Related Article
Ann. Thorac. Surg. 1996 61: 1118-1123.
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