Dr. Clarence Dennis
- Developed one of the first heart-lung machines
- Early oxygenator was designed on model of artificial kidney
- One of first open heart surgical procedures (April 1951) using extracorporeal circulation (although unsuccessful)
- Case was thought to be secundum ASD; turned out to be complete AV canal
Therefore, in the course of the same trip, I made a visit to Dr. Gibbon in his office. At that time he still had his equipment crated and had no hardware that he could show to me directly, but we had many very interesting discussions and Dr. Gibbon was very flattering in indicating his delight that somebody else had finally become interested in trying to work upon this problem. We exchanged ideas verbally at that time, became fast friends in the years that followed and had a standing understanding that we would exchange information between our respective laboratories, his in Philadelphia and mine in Minneapolis, so that neither one of us would have to duplicate the work the other had and so that the two of us might be able to get things done more quickly than would otherwise be possible. Funds, therefore, were sought in order to permit me and my associates to start this work at Minnesota. For some reason, we started out trying to get support from the United States Navy. We lost almost a year in this, at which time the authorities informed us that this was an excellent idea but they were sorry they had no money. I went therefore, on the advice of Dr. Wangensteen, to the National Institutes of Health and support was started July 1, 1947 and continued without interruption until the time of my departure from academic medicine in 1972.
Initially, we were much impressed by a visit of Dr. Willem Kolff at the University of Minnesota, during which Dr. Kolff had indicated that in his original cellulose tubing artificial kidney he noted that the venous blood that went in at one end and came out arterialized at the other. A duplicate of his artificial kidney was therefore constructed and was utilized as an oxygenator, only to discover that the amount of blood that could be oxygenated in this fashion was too small to be of any use if one were to try to divert the entire blood flow. We went ahead with our work and used one oxygenator after another. Some of them being duplicates of Gibbon, others being oxygenators that Dr. Karl E. Karlson and I devised upon our own. Dr. Karlson, in '47, had just returned from military duty, and he spent several years working with me on this until the time of his departure from the department with which I was concerned at Downstate, to go to Rhode Island, approximately 4 years ago. Along about 1949, Dr. Gibbon came to Minneapolis to visit, as he had done on many occasions.
At this time, for some reason, he seemed very pessimistic about what might be done. He came at the invitation not only of our laboratory, but of the Minneapolis Surgical Society which he addressed on the subject of "Respiratory Problems in Surgery", not on the question of "pumps and oxygenators." We matched our notes in the laboratory and he apparently became convinced that there was enough promise to justify going ahead in a vigorous fashion. He did just exactly that, as the whole world knows, and was successful in his first open heart case in 1953. This has always been a source of gratification to me that when he had accomplished this, he chose to publish it in Minnesota Medicine rather than one of the larger national journals.
In our own group in Minneapolis, we had considered ourselves ready to go ahead clinically early in 1951. Dr. Varco and one or two of his associates joined us in the laboratory. We had already done more than two dozen dogs in a row with a right atriotomy and closure without loss. Varco cooperated in several of these. We had our first patient in April 1951. This was a youngster, seven or eight years old, who had been explored in December of the preceding year by Dr. Varco with the thought that it was a lesion that might be reparable without having to go into the heart. He had put his finger in through the left atrial appendage and found a large defect which was interpreted as being an inter-atrial septal defect. This case, therefore, was considered a good one to utilize initially. At that time, cardiac catheterization facilities for establishing diagnoses in such cases were not yet generally available and were not used as far as this patient was concerned.
On April 5, 1951 this patient's chest was explored. The behavior of the oxygenator was most gratifying. Blood pressure was maintained satisfactorily. Flows were at a very high level through an unsuspected hematoma into the ear on which an oximeter devised by Earl Wood had been placed as an indicator of adequacy of perfusion. We, therefore, had flows over 200 ml./kg/minute during the course of the procedure. When the right heart was opened in order to try to make the necessary repair, it was found that this patient had a much more complicated lesion which neither Dr. Varco nor I recognized while the child was alive. The child, therefore, was lost on the table. Then it became apparent that this was an atrio-ventricular canal, a lesion which was not successfully handled in the operating room for another eight years. We had a second patient some four weeks later. This patient, in fact, proved to have a simple secundum type inter-atrial septal defect. It is one of the quirks of the way things sometimes go in an investigative area, that although we had spent a full year devising a level control apparatus in the oxygenator so as to avoid blowing oxygen into the aorta, the man running the machine was so concerned and so excited about the procedure that this device never was turned on and the patient died of gas embolization. This left us with very little likelihood of having more patients to work on in Minnesota. We had already made the agreement (Dr. Karlson and I) that we and some of our associates would move from the University of Minnesota to the State University of New York in Brooklyn.
We left in mid-summer and set up shop with a laboratory converted out of an abandoned funeral parlor across the street from Kings County Hospital, which proved to be a very satisfactory laboratory until permanent ones could be built. We had been much influenced in our decision to move by the fact that a pediatric cardiologist in Brooklyn had assured us of all support possible. This man had more than 160 possible candidates for repair under direct vision whom he was holding until such repair might be available. An adult cardiologist had assured us of full support as well. For reasons which are not clear to either Karlson or to me, even today, both of these men became a little less sure of themselves upon our arrival and we had no success in getting cases from either one of them. In 1953, as I have indicated already, Gibbon was successful with his first case. In 1955, Dr. Karlson, Dr. Stuckey and I were successful with our first open heart case. This patient went home and did very nicely and would have made excellent publicity except that she was a young lady in her late teens and celebrated her emancipation from heart disease by immediately becoming illegitimately pregnant so that she was not a very good candidate for that purpose. In the meantime, those of us in the laboratory looked for some other application of the apparatus that we had developed. One of the first ones that came along, or came to mind, was that of a patient with intractable left heart failure.
We found a small series of such patients and Dr. Melvin Newman was among the group that dealt with this group. And we had success with just an hour or two of support in getting these patients out of left ventricular failure, getting their lungs clear, returning good diuresis and satisfactory weight loss. Inasmuch as there had at that time not yet been any successful means derived for dealing with valvular heart disease, these patients enjoyed only temporary improvement. Therefore, it seemed reasonable to look for some type of lesion that might be reversible upon simple rest of much of the myocardium. And the idea occurred to me that the patient with a massive myocardial infarction and shock might be such a candidate. The first patient whom we had in this category came to us in February 1957. He had been in the hospital approximately 28 hours when he came to us and had vigorous medical therapy utilizing vasopressors, and so forth. His response to the medical management had been unsatisfactory and he came to us and was placed on partial cardiopulmonary bypass for a period of about 4 hours. It is interesting that our equipment was poor enough still so that the driving reason for taking him off of support was hematuria. Nevertheless, he made a satisfactory recovery even though it was a very slow and very painful. That patient is still alive today and still runs his own haberdashery store in Brooklyn.
We had two other patients with acute myocardial infarction and shock who were handled in a similar fashion. One of them appeared to be following the same sort of course, but following his transfer away from our own service some 10 days after perfusion, he became disoriented while not being closely watched in the middle of the night, ran down the hallway and collapsed. He could not be resuscitated. The third patient died about 36 hours after perfusion. At autopsy, the entire left ventricle was involved with infarction. It is perplexing he went as long as he did.
With this material being brought to the attention of the profession, our group was criticized by several. Dr. Peter Salisbury from the West Coast had done some experimental work in animals suggesting that the degree of pulmonary edema might be actually increased by cardiopulmonary bypass, and he had some documented experiments in which left atrial pressure had actually risen upon institution of such support. Then Sarnoff and Braunwald and their associates had in 1957 published a very nice paper on the "Determinance of Oxygen Utilization of the Left Ventricle" and come to the conclusion that the primary factor dictating the oxygen utilization is the pressure against which the left ventricle must empty. Their argument was that inasmuch as we had done nothing to lower the pressure in the aorta and inasmuch as we did not take all of the blood that comes to the left ventricle, therefore, we could not really be expected to be successful in reducing the actual amount of work which the left ventricle must do. They even suggested that the only reason for survival was that we had provided better perfusion for the rest of the body and perhaps, through the coronaries, better perfusion for the myocardium. After thinking about this for a while, the opportunity became available to me to take a year of sabbatical leave.
I, therefore, chose to work with Professor Clarence Crafoord and now Professor Ake Senning at the Karolinska Institute in Stockholm. During the year that I spent there, it was possible to demonstrate that on left heart bypass one could cut the oxygen utilization of the left ventricle almost in half without changing the mean pressure of the aorta. Being encouraged with this, Dr. Senning, Dr. David Hall (now of Georgia) and several other collaborators devised a cannula to be placed down the right internal jugular vein through the atrial septum and into the left atrium. This permitted us to perform left ventricular bypass without opening the chest. This seemed as though it might be a good means of providing support for patients with myocardial infarction and shock. One of the things which seemed most promising about it was that it should relieve pulmonary edema very quickly. We used it on a series of approximately 25 patients. Only the first two of them at Karolinska Institute while I was there; others subsequent to my departure, both there and in Brooklyn.
We learned very quickly that those patients in pulmonary edema with myocardial infarction and shock could have the edema cleared within 12 to 15 minutes. This was a very gratifying development. Nevertheless, of the 15 or 16 patients with myocardial infarction and shock, there were no long-term survivors. The reasons for this are several. There were two or three patients who were taken off of left heart bypass, apparently on the road to recovery, only to die within hours or a day or two after, presumably with extension of the area of infarction. There were others in the series, especially late in the course of our experience, whose death I think was preordained inasmuch as the cardiologists apparently with considerable fear because of this "sword swallowing" maneuver, and because there had been no long term survivors, came to the decision that we should not be utilizing this technique on patients unless they were in a stage in which recovery could not otherwise be expected. Our first two, for instance, did not come to us until after the electroencephalograms had become entirely flat. It seemed to the group of us, therefore, that this was not a fruitful endeavor to pursue until the situation could be clarified. It is possible today, with the intra-aortic balloon pumping, that enough cardiologists are convinced of the virtues of support so that this procedure might conceivably be rejuvenated.
WGR: Clarence, could I interrupt at this point and ask a couple of questions?
1. Along the lines of what you just said, comparing left atrial entry and left ventricular bypass, with all of the other means of cardiac support that we have now, don't you think that it has about the best physiologic basis for this particular application?
CD: I think it does. The trouble with it is, though, that it takes a great deal more dissection and consumes considerably more time to put a patient on a closed chest, left ventricular bypass than it does to put a patient on an intra-aortic type of support. It is true that one can take four or five liters a minute from the left atrium of the patient and bypass that amount. While it is true that insofar as we can determine flow from looking through the literature and comparing data, the maximum equivalent of support that one can get with an intra-aortic balloon is, for an adult patient, approximately a liter and a half per minute. So that it does seem that some sort of bypass would be more effective.
Today, however, now that we have excellent membrane oxygenators which can be utilized for many hours or even days without serious detriment to the patient, it seems so much simpler to use femoro-femoral arteriovenous bypass (veno-arterial bypass with oxygenation) that utilization of the left heart bypass for emergency purposes does not seem to be a sensible course to follow.
Back to the clinical utilization of the left heart bypass system, my former associate, Dr. Richard Cappelletti, following his completion of his training and departure to elsewhere in New York City, utilized a left heart bypass on a series of patients (I believe 8 in number). Three of these were patients with myocardial infarction and shock. One of those who lived a day and then died was one of these. There were, in this group of patients, four who had serious indications for emergency laparotomy but who were suffering from chronic left heart failure that was resistant to medical management. Cappelletti carried three of these four patients through to successful outcome by utilizing left heart bypass for support during the exploratory laparotomies in question. Another patient had acute left ventricular failure without infarction. This patient responded very nicely and did very nicely thereafter. It did not hurt Cappelletti that the man happened to be the President of the Board of the hospital in which he worked.
Now, other things have developed in the course of the work in the laboratories with which I personally did not have nearly as much to do as I did with left heart bypass and with pump oxygenators. One of those is the immense amount of work done by Jackson H. Stuckey and Brian Hoffman and Paul Cranefield. Hoffman and Cranefield wee in the department of physiology at Downstate and Stuckey, of course, was in the department of surgery. This team did so much work on the processes of myocardial activation in the course of the normal pulse beat that they required rewriting of much of the work in the literature on electrocardiography. Among the things which Dr. Hoffman and Stuckey succeeded in doing was to identify the Bundle of His in an electrical manner in the course of open heart operations. There were not large enough series of patients at Downstate to give this proper credence and the matter has now been picked up by Dr. Malm, with whom Dr. Hoffman now works at Columbia/Presbyterian at the present time. The technician, Mr. Samuel Moss, who had been with us at Downstate, is now also at Columbia/Presbyterian. This team has run about 65 patients with lesions requiring precise identification of the Bundle of His in whom there is enough uncertainty in the lesions in question that it is, in Dr. Malm's opinion, absolutely essential to have this sort of guidance in order to avoid injury to the Bundle. Another pattern of study that came out of this laboratory was that of external-compression counterpulsation. This idea had occurred to me and I had worked on it a little before going to Stockholm in1960.
During the year in Stockholm a fair amount of work was done on this and the early papers carried the name of Ake Senning, as well as the group of us from Brooklyn. The work was carried on so as to indicate that we could do approximately as well as with the other type of counterpulsation. And, indeed, the N.I.H. obtained a patent on this in my name which has assisted the N.I.H. in making sure that the technique is not used in fashions which are not in the interest of patients, a situation which would be nice in many other types of new surgical techniques which should become available. I personally gave up external-compression counterpulsation in the belief that if there were enough arterial disease so that there was embarrassment of the coronary circulation, it probably was enough generalized arterial disease so the compressibility of the arteries in the extremities would seriously be in question. This opinion was enhanced by the frequency of the observation that one would have to go to a second femoral vessel for left heart bypass in order to have a vessel big enough or open enough for a return of blood. Another study that gives me great satisfaction is that of Dr. Russell Nelson, now at the Latter Day Saints Hospital in Salt Lake City. While Dr. Nelson was in the laboratory with me at the University of Minnesota, he opened up the whole field of gram negative septic shock based upon contamination in one of the early machines that we used. I played no part in this at all; in fact, had I not been away from the city for two weeks, Dr. Nelson would not have had the freedom to solve the whole problem. It was not until many months after this that Dr. Jacob Fine and his associates in Boston had started working on this particular area. Nelson deserves a great deal of acclaim for this work for which, somehow, he does not seem to ever see as much as it might seem to be in order.
Another field in which our group was much interested in was that of the development of synthetic valves to replace diseased valves in patients. We had a ball valve (ball-in-the-cage valve) which was placed in the mitral orifice in dogs. The longest survivor was approximately three months, and this dog had so many infarcts to the kidneys that he died in uremia. We had an occasional dog who had embolization of the ball, but this appeared to us to be simply a technical matter that might be overcome. We were unsuccessful in making the ball valve that would not require continuing heparinization and it was our conviction that continuing heparinization would be so fraught with hemorrhagic problems that we dropped the matter. Dr. uh (Oh dear, what's his name?) Starr, Dr. Alvin Starr on the West Coast, picked this matter up several years later and demonstrated that continuing heparinization was possible in the dog and that it could be utilized clinically, a situation which he had not planned ahead of time but had fallen into in the course of attempts to repair the mitral valve on a patient who could not have gotten off the table at all had he not replaced that mitral valve.
Another area in which the people in the laboratory were very much involved was that of the development of the technique of gas endarterectomy. This was the idea of Dr. Sol Sobel, in the first place, a member of the old open division of the Kings County Hospital but a very devoted and a very hard working member of the University faculty after they all became one. He and Dr. Kaplitt and Dr. Phillip Sawyer worked together, and I joined with them in developing the area of gas endarterectomy for coronary arterial obstruction. This technique has had a measure of success in other hands. It still is being used extensively by Dr. Kaplitt at the North Shore Hospital, where it is used primarily for coronary arterial disease to open up a large drainage bed where there is not enough flow otherwise to justify doing an aortocoronary bypass. It will take a long series of patients to demonstrate whether this technique will stand up in the long run.
Now, in the course of the work in the laboratory, many ideas have come from many people. It has been one of my greatest sources of satisfaction in an academic career to have been associated with so many people who have had so many ideas and contributed so much to the success of the entire group. Among these, of course, are not only surgeons but also physiologists from the top to the bottom of the departments concerned both at Minnesota and at State University of New York. There have been engineers, there have been technicians, there have been nurses, and there have been medical students, members of the surgical house staff and many others. And I wish to take this occasion to indicate my appreciation to all of these people who have contributed so much. I think there is a perhaps sort of an after-thought in talking about all of this. I should indicate that through the kindness of Dr. Charles Hufnagel, I had the opportunity to speak with Colonel Charles Lindbergh (I believe, General now, isn't it? Charles Lindbergh.
WGR: Whatever it is, it is “retired”.
CD: Yes. At Georgetown University Hospital about six months ago, I asked General Lindbergh what his reason had been for becoming interested in making the perfusion pump which he and Dr. Carrel published in 1932. I believe it was. General Lindbergh indicated that in 1930, or perhaps a little before, he had a sister-in-law with multiple valvular disease and that the cardiologist had indicated that there was nothing that could be done for this. He, therefore, conceived the idea of making a pump oxygenator so that the heart could be opened, the valves could be inspected, and proper repair on those valves could be performed. He toured the country looking for people who might be able to join with him or give him some sort of support: intellectual, scientific and so forth, so that he might be able to do this. He came ultimately to Dr. Carrel in New York City. Dr. Carrel explained to General Lindbergh that the problem was a fascinating one and would be extremely useful but that at that time there was not yet any satisfactory way of preventing the blood from clotting as it passed through the artificial orifice. Carrel, therefore, had convinced Lindbergh that the next best thing that they could do together would be to make a pump for pumping perfusion fluids through individual organs. Perhaps as a further tribute to Dr. Gibbon, it was within a year of that time that heparin became available that Gibbon saw fit to embark upon the attempt to make a pump oxygenator. This is a nice example, not only as serendipity, but also of very high intelligence.
WGR: Clarence, thank you very much. I would like to ask you one or two very brief questions in closing.
1. At the time you embarked on the development of a pump oxygenator, how did the time of development of the wide application fit in with your predications at that time? Did it come along faster than you thought? Slower than you thought? Or just which of these?
CD: I think it was a little more slow in coming than I had thought that it might be. As a matter of fact, I can remember discussing this with multiple people. I talked with Jonathan Rhodes in 1950 and he asked me if I really seriously thought that this was a technique that might ever become feasible. And I said, "Yes, I really did. I thought that it would work." And I think Jonathan was a little bit skeptical about this and he ended by saying, "Well, the quickest one will have it, is that right?" And I said, "Yes, I think that is right". Well, the quickest man was Jack Gibbon.
WGR: Very good. Dr. Dennis, thank you so very much. We appreciate your being here and we appreciate the opportunity of having these personal thoughts of yours recorded for our project.