The development of the heart-lung machine made repair of intracardiac lesions possible. Lillehei wrote, “A physician at the bedside of a child dying of an intracardiac malformation as recently as 1952 could only pray for a recovery! Today with the heart-lung machine, correction is routine.” [68 ] To bypass the heart, one needs a basic understanding of physiology of the circulation, a method of preventing the blood from clotting, a pump to pump blood, and finally, a method to ventilate the blood.
During the last century, physiologists were interested in isolated organ perfusion and therefore needed a method to oxygenate blood. Von Frey and Gruber [69 ] described a blood pump in 1885 in which gas exchange occurred as blood flowed into a thin film over the inner surface of a slanted rotating cylinder. In 1895 Jacobi passed blood through an excised animal's lung that was aerated by artificial respiration. [70 ] In 1926, Professors S. S. Brukhonenko and S. Tchetchuline [71 ] in Russia designed a machine that used an excised lung from a donor animal as an oxygenator and two mechanically actuated blood pumps. Their machine was used initially to perfuse isolated organs but later was used to perfuse entire animals.
Alexis Carrel, a Nobel laureate, and Charles Lindbergh, the famous aviator, developed a device that successfully perfused the thyroid gland of a cat for 18 days, beginning April 5, 1935. [72 ] A picture of the two investigators with their perfusion apparatus appeared on the July 1, 1935 cover of Time Magazine . [73 ] At the end of that time, much of the tissue was partially preserved, and pieces grew epithelial cells in tissue culture. According to Edwards and Edwards, [72 ] many other organs were perfused over the next few years by Carrel and Lindbergh. Hearts were kept beating for several days. Although perfused organs survived surprisingly well, all showed progressive degenerative changes in a few days. Edema fluid filled tissue spaces, arteries became calcified, and connective tissue cells outgrew the more specialized cells.
One of the key requirements of the heart-lung machine was anticoagulation. Heparin was discovered by a medical student, Jay McLean, working in the laboratory of Dr. William Howell, a physiologist at Johns Hopkins. [74 ] In 1915 Howell gave McLean the task of studying a crude brain extract known to be a powerful thromboplastin. Howell believed that the thromboplastic activity was caused by cephalin contained in the extract. McLean's job was to fractionate the extract and purify the cephalin. McLean also studied extracts prepared from heart and liver. McLean discovered that a substance in the extract was retarding coagulation. McLean wrote [75 ] :
I went one morning to the door of Dr. Howell's office, and standing there (he was seated at his desk), I said, “Dr. Howell, I have discovered antithrombin.” He smiled and said, “Antithrombin is a protein and you are working with phospholipids. Are you sure that salt is not contaminating your substance?”. . . I told him that I was not sure of that, but it was a powerful anticoagulant. He was most skeptical, so I had the diener, John Schweinhand, bleed a cat. Into a small beaker full of its blood, I stirred all of the proven batch of heparphosphotides, and placed this on Dr. Howell's laboratory table and asked him to tell when it clotted. It never did.
McLean described his finding in February 1916 at a medical society meeting in Philadelphia and later reported it in an article entitled, “The Thromboplastic Action of Cephalin.” [75 ] , [76 ] Howell and Holt [77 ] reported their work on heparin in 1918. In the 1920s, animal experiments confirmed that heparin was an effective anticoagulant. [78 ]
John Gibbon probably contributed more to the success of the development of the heart-lung machine than anyone else. His interest began one night in 1931 in Boston “during an all-night vigil by the side of a patient with a massive embolus. . .” [79 ] :
My job that night was to take the patient's blood pressure and pulse every 15 minutes and plot it on a chart. During the 17 hours by the patient's side, the thought constantly recurred that the patient's hazardous condition could be improved if some of the blue blood in the patient's distended veins could be continuously withdrawn into an apparatus where the blood could pick up oxygen and discharge carbon dioxide and then pump this blood into the patient's arteries. At 8 a.m. the patient's blood pressure could not be measured. Dr. Edward Churchill; the chief of surgery, immediately opened the chest through an anterior left thoracotomy, then occluded both the pulmonary artery and the aorta as they exited from the heart. He opened the pulmonary artery and removed massive blood clots. The patient did not survive.
In 1937, Gibbon reported the first successful demonstration that life could be maintained by an artificial heart and lung and that the native heart and lungs could resume function. Unfortunately, only three animals recovered adequate cardiorespiratory function after total pulmonary artery occlusion and bypass, and even they died a few hours later. [80 ] Gibbon's work was interrupted by World War II; afterwards, he resumed his work at the Thomas Jefferson Medical College in Philadelphia. Meanwhile, other groups, including Clarence Crafoord in Stockholm, Sweden, J. Jongbloed at the University of Utrecht in Holland, Clarence Dennis at the University of Minnesota, Mario Dogliotti and coworkers at the University of Turino in Italy, and Forrest Dodrill at Harper Hospital in Detroit, also worked on a heart-lung machine. [81 ]
Clarence Dennis's first clinical attempt at open heart surgery was in a 6-year-old girl with end-stage cardiac disease. [82 ] Her heart was already massive, and her only hope was surgical closure of an atrial septal defect. At operation on April 5, 1951, her circulation was supported by a heart-lung machine that Dennis and coworkers had developed. [83 ] The atrial septal defect was very difficult to close. Although the heart-lung machine functioned well, the patient did not survive, probably because of a combination of blood loss and surgically induced tricuspid stenosis.
In August of 1951, Mario Digliotti used his heart-lung machine to support the circulation in a 49-year-old patient during resection of a large mediastinal tumor. [84 ] During the operation, the patient developed hypotension and cyanosis. He was placed on partial bypass at 1 liter/min. Although the mass was resected successfully, the Italian machine was never used for open heart surgery in humans.
Forrest Dodrill and colleagues used the mechanical blood pump they developed with General Motors on a 41-year-old man. [85 ] The machine was used to substitute for the left ventricle for 50 minutes while a surgical procedure was carried out on the mitral valve. Although Dodrill's report lacks details of the procedure and omits important hemodynamic information, it nevertheless represents a landmark in the field of cardiothoracic surgery. This, the first clinically successful total left-sided heart bypass, was done July 3, 1952 and followed from Dodrill's experimental work with a mechanical pump for univentricular, biventricular, or cardiopulmonary bypass. Although Dodrill et al. had used their pump with an oxygenator for total heart bypass in animals, [86 ] they felt that left-sided heart bypass was the most practical method for their first clinical case because it was not associated with a profound “hypotensive reflex” that occurred in other forms of bypass. When their patient was interviewed at age 68, he recalled seeing dogs romping on the roof of a nearby building from his hospital room in 1952. Later he learned that they had been used in the final test of the Dodrill-General Motors mechanical heart machine.
Later, on October 21, 1952, Dodrill et al. used their machine in a 16-year-old boy with congenital pulmonary stenosis to perform a pulmonary valvuloplasty under direct vision; this was the first successful right-sided heart bypass. [87 ]
Hypothermia was another method to stop and open the heart. In 1950, Bigelow et al. [88 ] reported on 20 dogs that had been cooled to 20°C, with 15 minutes of circulatory arrest; 11 animals also had a cardiotomy. Only 6 animals survived after rewarming. Bigelow and colleagues continued to study hypothermia [89 ] , [90 ] and hibernation and learned that a groundhog could be cooled to a body temperature of 5°C and be revived. This temperature allowed circulatory arrest and cardiotomy for 2 hours without ill effects. [91 ]
In 1953, F. J. Lewis and M. Taufic reported on 26 dogs that had surgically induced atrial septal defects which they attempted to close using a hypothermia technique. In this paper, the authors also reported a 5-year-old girl who had closure of her atrial septal defect on September 2, 1952 using a hypothermic technique. [92 ]
She was anesthetized with pentothal sodium and curare and the trachea was intubated. She was then wrapped in refrigerated blankets until after a period of two hours and ten minutes her rectal temperature had fallen to 28o. At this point the chest was entered through the bed of the right fifth rib. The cardiac inflow was occluded for a total of five and one-half minutes and during this time the septal defect measuring 2 cm in diameter was closed under direct vision. The patient was rewarmed by placing her in hot water kept at 45°C and after 35 minutes her rectal temperature had risen to 36°C at which time she was removed from the bath. Recovery from the anesthesia was prompt and her subsequent postoperative convalescence was uneventful.
The Louis-Taufic article describes the first successful repair of an atrial septal defect with surface cooling under direct vision. Shortly after, Swan et al. [93 ] reported successful results in 13 clinical cases using a similar technique. However, use of systemic hypothermia for open intracardiac surgery was relatively short-lived. After the heart-lung machine was introduced clinically, it appeared that deep hypothermia was obsolete. However, during the 1960s it became apparent that operative results in infants under 1 year of age using cardiopulmonary bypass were poor. In 1967, Hikasa et al., [94 ] from Kyoto, Japan, published an article that reintroduced profound hypothermia for cardiac surgery in infants and used the heart-lung machine for rewarming. Their technique involved surface cooling to 20°C, cardiac surgery during circulatory arrest for 15 to 75 minutes, and rewarming with cardiopulmonary bypass. At the same time, other groups reported using profound hypothermia with circulatory arrest in infants with the heart-lung machine for cooling and rewarming. [95 ] – [98 ] Results were much improved, and subsequently the technique also was applied for resection of aortic arch aneurysms.
After World War II, John Gibbon resumed his research. He eventually met Thomas Watson, chairman of the board of the International Business Machines (IBM) Corporation. Watson was fascinated by Gibbon's research and promised help. Soon afterward, six IBM engineers arrived and built a machine that was similar to Gibbon's earlier machine, which contained a rotating vertical cylinder oxygenator and a modified DeBakey rotary pump (Fig. 1-4) . Gibbon successfully used this new machine for intercardiac surgery on small dogs and had several long-term survivors, but the blood oxygenator was too small for patients. Eventually, the team developed a larger oxygenator that the IBM engineers incorporated into a new machine. [99 ]
In 1949, Gibbon's early mortality in dogs was 80 percent, but it gradually improved. [81 ] The first patient was a 15-month-old girl with severe congestive heart failure. The preoperative diagnosis was atrial septal defect, but at operation, none was found. She died, and a huge patent ductus was found at autopsy. The second patient was an 18-year-old girl with congestive heart failure also due to an atrial septal defect. This defect was closed successfully on May 6, 1953 with the Gibbon-IBM heart-lung machine. The patient recovered, and several months later the defect was confirmed closed at cardiac catheterization. [100 ] Unfortunately, Gibbon's next two patients did not survive intracardiac procedures when the heart-lung machine was used. These failures distressed Dr. Gibbon, who declared a 1-year moratorium for the heart-lung machine until more work could be done to solve the problems causing the deaths.
During this period, C. Walton Lillehei and colleagues at the University of Minnesota studied a technique called controlled cross-circulation . With this technique the circulation of one dog was temporarily used to support that of a second dog while the second dog's heart was temporarily stopped and opened. After a simulated repair in the second dog, the animals were disconnected and allowed to recover. Lillehei remarked [68 ] :
Clinical cross-circulation for intracardiac surgery was an immense departure from the established surgical practice. This thought of taking a normal human to the operating room to serve as a donor circulation (with potential risk, however small) even temporarily was considered by critics at that time to be unacceptable, even “immoral” as one prominent surgeon was heard to say. Some others, skilled in the art of criticism were quick to point out that this proposed operation was the first in all of surgical history to have the potential (even the probability in their judgment) for a 200 percent mortality.
However the continued lack of any success in the other centers around the world that were working actively on heart-lung bypass made the decision to go ahead inevitable. I felt the technique was ready to use in man; however even in such a progressive and pioneering medical school as Minnesota University, there was opposition to the idea. Dr. Owen Wangenstein, Chairman of the Department of Surgery, was a tremendous help. He was well aware of these experiments and whole-heartedly supported them. Where there seemed a possibility that the first clinical operation might be canceled the night before because of this opposition, I left a note for Dr. Wagenstein asking, “Is our case still on in the morning?” His answer, “Dear Walt-By all means, go ahead.”
Lillehei et al. [101 ] used their technique at the University of Minnesota to correct a ventricular septal defect in a 12-month-old infant on March 26, 1954 (Fig. 1-5) . The patient had been hospitalized 10 months for uncontrollable heart failure and pneumonitis. At operation, a 2-cm membranous ventricular septal defect (VSD) was closed with suture. The patient made an uneventful recovery until death on the eleventh postoperative day from a rapidly progressing tracheal bronchitis. At autopsy, the VSD was closed, and the respiratory infection was confirmed as the cause of death. Two weeks later the second and third patients had VSDs closed by the same technique 3 days apart. Both remained long-term survivors with normal hemodynamics confirmed by cardiac catheterization.
In 1955 Lillehei et al. [102 ] published a report of 32 patients that included repairs of ventricular septal defects, tetralogy of Fallot, and atrioventricularis communis defects. By July of 1955, the blood pump used for systemic cross-circulation by Lillehei et al. was coupled with a bubble oxygenator developed by Drs. DeWall and Lillehei, and cross-circulation was abandoned after use in 45 patients during 1954 and 1955. Although its clinical use was short-lived, cross-circulation was an important stepping stone in the development of cardiac surgery. [68 ]
Meanwhile, at the Mayo Clinic only 90 miles away, John W. Kirklin and colleagues launched their open heart program on March 5, 1955. [103 ] They used a heart-lung machine based on the Gibbon-IBM machine, but with their own modifications. Dr. Kirklin wrote [104 ] :
In 1951, now on the surgical staff of the Mayo Clinic I did a closed pulmonary valvulotomy on a 30-year-old man with pulmonary stenosis and intact ventricular septum. He had massive ventricular hypertrophy and died about two days after the operation. At autopsy it was apparent that the pulmonary valve was open, but also that the subvalvular muscle hypertrophy was enormous. The patient could not survive without relief of the muscular obstruction. Dr. Earl Wood, a great physiologist and my co-worker and I went back to his office after we viewed that autopsy and decided that we would either have to be content with cardiac surgery as a rather minor specialty, limited to passing instruments into the heart or we would need a heart-lung machine. In earlier times, Earl Wood had worked with Maurice Vissher at the University of Minnesota and had extensive experience with the Starling heart-lung preparation. “It's the oxygenator that is the problem,” said Earl Wood.
We investigated and visited the groups working intensively with the mechanical pump oxygenators. We visited Dr. Gibbon in his laboratories in Philadelphia, and Dr. Forrest Dodrill in Detroit, among others. The Gibbon pump oxygenator had been developed and made by the International Business Machine Corporation and looked quite a bit like a computer. Dr. Dodrill's heart-lung machine had been developed and built for him by General Motors and it looked a great deal like a car engine. We came home, reflected and decided to try to persuade the Mayo Clinic to let us build a pump oxygenator similar to the Gibbon machine, but somewhat different. We already had had about a year's experience in the animal laboratory with David Donald using a simple pump and bubble oxygenator when we set about very early in 1953, the laborious task of building a Mayo-Gibbon pump oxygenator and continuing the laboratory research.
Most people were very discouraged with the laboratory progress. The American Heart Association and the National Institutes of Health had stopped funding any projects for the study of heart-lung machines, because it was felt that the problem was physiologically insurmountable. David Donald and I undertook a series of laboratory experiments lasting about a year and a half during which time the engineering shops at the Mayo Clinic constructed a pump oxygenator based on the Gibbon model. [105 ]
Of course a number of visitors came our way and some of them came to the laboratory to see what we were doing. [104 ] One of those visitors was Ake Senning (from Stockholm, Sweden). I still remember one day when he was there and one of the connectors came loose and we ruined his beautiful suit as well as the ceiling of the laboratory by spraying blood all around the room.
The electrifying day came in the spring of 1954 when the newspapers carried an account of Walt Lillehei's successful open heart operation on a small child. Of course, I was terribly envious and yet I was terribly admiring at the same moment. That admiration increased exponentially when a short time later, a few of my colleagues and I visited Minneapolis and observed one of what was now a series of successful open heart operations with control cross-circulation. Walt then took us on rounds and it was absolutely exciting to see small children recovering from these miraculous operations, however it was also for a time, a difficult period for me. Some of my colleagues at the Mayo Clinic, and some of my influential ones, indicated to me that we had wasted much time and money. After all, this young fellow in Minneapolis was successful with a very simple apparatus and did not even require an oxygenator. Visitors coming from Minneapolis to Rochester asked, “What are you working on these days?” When I said we were working with an integrated pump oxygenator, most said, “Oh, yes, but I understand even Gibbon has given that up.” As the months went by and my anxiety grew and I worried that we too might not make the effort a successful one. My apprehension was heightened early in 1955 when Time Magazine published an interview with Dick Varco who described all too accurately the damaging effects of artificial oxygenators and why they were impractical and dangerous.
However in the winter of 1954 and 1955 we had 9 surviving dogs out of 10 cardiopulmonary bypass runs. With my wonderful colleague and pediatric cardiologist, Jim DuShane, we had earlier selected 8 patients for intracardiac repair. Two had to be put off because two babies with very serious congenital heart disease came along and we decided to fit them into the schedule. We had determined to do all 8 patients even if the first 7 died. All of this was planned with the knowledge and approval of the governance of the Mayo Clinic. Our plan was then to return to the laboratory and spend the next 6 to 12 months solving the problems that had arisen in the first planned clinical trial of a pump oxygenator. Gibbon, of course, had done a successful case in 1953, but it was an isolated case and the next four patients died. In the deepest recesses of my heart, I felt that those four patients died in part because of the lack of appreciation of some of the technical aspects of the cardiac surgery.
We did our first open heart operation on a Tuesday in March 1955. That evening I had a telephone call from Dick Varco in Minneapolis who indicated that Sir Russell Brock was visiting their cardiac surgical program at the University of Minnesota at that time. Walt Lillehei and Dick Varco indicated to Sir Russell that we had done the operation earlier that day and they called to see if he could come to Rochester the next day to see the patient of which I said “Certainly.” I was afraid that they would ask if we planned to do another case, and they did. I replied, “Yes, and we will be doing another case on Thursday.” They asked if Sir Russell could watch the operation. Well, as you can imagine, I had enough on my mind without having a world-famous surgeon sitting in the gallery watching this young guy try to work his way through his second open heart operation. However, we acceded to Sir Russell's coming and I am happy to say he was a marvelous guest during the second operation, and the patient did well as had the first one.
Four of our first 8 patients survived, but the press of the clinical work prevented our ever being able to return to the laboratory with the force that we had planned. By now, Walt Lillehei and I were on parallel, but intertwined paths. I witnessed an earlier parallel pathway existing between Dwight Harken and Charles Bailey in the first days of closed mitral valve surgery. I felt, and I hope you will forgive me, that their interactions were in some ways demeaning to themselves and to the scientific progress of cardiac surgery. I am extremely grateful to Walt Lillehei and am very proud for the two of us, that during that 12 to 18 months when we were the only surgeons in the world performing open intracardiac operations with cardiopulmonary bypass and surely in intense competition with each other, we shared our gains and losses with each other. We continued to communicate and we argued privately in nightclubs and on airplanes rather than publicly over our differences. Walt was more cheerful and more optimistic than I when we discussed problems. I remember saying to him one day, “Walt, I am so discouraged with complete atrial ventricular canal.” “Oh, sure,” he said, “that is a tough lesion, but we will learn to do well with it.”
By the end of 1956, many university groups around the world had launched into open heart programs. Currently, it is estimated that more than 500,000 cardiac operations are performed each year worldwide with the use of the heart-lung machine. In most cases, the operative mortality is quite low, approaching 1 percent for some operations. Little thought is given to the courageous pioneers in the 1950s whose monumental contributions made all this possible.