The development of cardiopulmonary bypass or a machine that could temporarily take over the function of the heart and provide oxygenation of the blood (bypass the pulmonary circuit) was a major development in clinical medicine. With the ability to bypass both the heart and lungs, surgeons were now able to correct cardiac defects, replace diseased valves, and bypass obstructed coronary arteries. It has led to the ability to remove the heart itself, and perform a transplant.

It has also been instrumental in the development of ventricular assist devices, which can be implanted on a temporary or permanent basis, to provide partial or complete perfusion for the entire body.

This development was initiated in the early 1800s when physicians were experimenting with forms of external perfusion, which meant drawing blood from a living animal or person and injecting it into an excised organ or subject. The external perfusion techniques soon led to processes which infused oxygen into the perfused blood. However, it was not until Dr. Gibbon’s development of the heart-lung machine in the 1950s that the dreams and aspirations of the early visionaries were realized.

In 1812, Cesar-Julian-Jean LeGallois (1) postulated that tissues and organs of dead animals could be returned to a functioning living state by restoring blood flow via a perfusion machine. This theory was based on experiments which had restored function to organs of dead animals by perfusing their organs with blood. The perfusion was by hand syringe. Similar studies followed, such as artificial perfusion of muscles and organs. In the 1850s, Charles Eduard Brown-Sequard (2) attributed the success of these perfusions of muscles and organs to oxygenated blood. He made the observation that rigor mortis temporarily disappeared from the muscles of guillotined criminals when these muscles were perfused with their own blood. His techniques for perfusing organs were rather simple—he used syringes for perfusion, and introduced oxygen into the blood by agitating the blood vigorously. Other investigators at that time, such as Waldemar Von Schroder (3), used a bubbling method or passing bubbles of air or oxygen through the blood in an attempt to increase the oxygen in these primitive perfusion systems. Unfortunately, the bubble technique resulted in significant foaming in the blood and gas embolism. The solution would await the development of antifoaming agents in the following century.

Another technique was used for introducing oxygen into the blood—the filming technique, which was developed in 1885 by Max Von Frey and Max Gruber. They were able to oxygenate blood by running blood inside a rotating cylinder filled with oxygen (4). They used this device for the perfusion of isolated organs. Other investigators at that time were also using a filming technique to oxygenate blood in their experimental apparatus. Richards and Drinker (5) directed the blood flow through a cloth cylinder inside an oxygen chamber, and Baylis dispersed the blood over a series of disks and cones and then oxygenated over with flowing oxygen (6,7). Other researchers dispersed the blood on a glass cylinder into which oxygen jets were blowing. Nevertheless, oxygenating the blood for these perfusion studies remained a difficult problem to overcome. The apparatus were very complex, utilizing very low volumes of blood per minute, and they could be maintained for only short time periods.

Investigators such as Patterson and Starling (8) and Jacob (9) oxygenated the blood by having it first perfuse through the animal’s own lungs and then into the investigated organ. In that way the blood was being auto-oxygenated. These devices were cleverly designed, but very difficult to maintain.

These efforts at organ perfusion were taken to another level by the Russian duo Brukhonenko and Tchetchuline (10), who perfused oxygenated blood through the carotid arteries of guillotined heads of dogs, and were able to keep the head functional for several hours. The blood that was being infused into the carotid arteries was being oxygenated through the lungs of a second dog (see Fig 1.2). These experiments foreshadowed the cross-circulation work of Dr. Walt Lillehei at the University of Minnesota (10), decades later, in which he used the parent of a child as both pump and oxygenator for pediatric patients undergoing cardiac surgery.

After success with keeping the dog heads functional for several hours, Brukhonenko used a similar method of
oxygenation in an attempt to bypass the nonfunctioning hearts of dogs. Although some of these animals lived for a short period of time after termination of the experiments, he was not able to restore heart function. These studies by Brukhonenko (11) were unsuccessful, but suggested how a bypass device with an oxygenator had potential applications in humans. His foresight at this juncture regarding the possibility of being able to bypass the heart was far ahead of its time (12).

The famous aviator, Charles Lindbergh, was also involved in the research related to the heart pump. Mr. Lindbergh’s sister-in-law had rheumatic fever, and at that time there were no operations for the correction of a diseased heart valve. In an effort to design a mechanical heart that would maintain blood circulation while his sister-in-law’s heart was being operating on, he continually queried doctors, which eventually led to a meeting with Dr. Alexis Carrell, winner of the Nobel Prize and the director of the Rockefeller Institute for medical research (13). Dr. Lindbergh discussed his ideas with Carrell, and the potential problems such as infection, blood clotting, and hemolysis of red blood cells. Carrell was very interested in tissue culture perfusion and made the point that he had not been successful in finding an infection-free organ-perfusing device. Following these conversations, Lindbergh went to work part-time at the Rockefeller Institute in New York. He worked on trying to perfuse whole organs and was able to develop a sterile pulsatile perfusion system which could work at various flow rates and variable perfusion pressures. This work led to a picture of Carrell (13) and Lindbergh on the cover of Time magazine in June 1938. This pump system was able to perfuse various organs for multiple days, including a thyroid gland for 18 days in 1935 (14). They were able to grow epithelial cells of the organ in tissue cultures after that perfusion period. They were also able to keep hearts beating for several days with the pumps that they developed. These organs survived well over several days, but developed interstitial edema.

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” (12). To bypass the heart, one needs a basic understanding of the 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.

One of the key requirements of the heart-lung machine is anticoagulation of blood. Heparin was discovered by a medical student, Jay McLean, working in the laboratory of Dr. William Howell, a physiologist at Johns Hopkins (15). 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 (16) wrote:

McLean described his finding in February 1916 at a medical society meeting in Philadelphia and later reported it in an article titled “The Thromboplastic Action of Cephalin” (16,17). Howell and Holt (18) reported their work on heparin in 1918. In the 1920s, animal experiments confirmed that heparin was an effective anticoagulant (19).

John Gibbon (20) 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:

Gibbon’s work on the heart-lung machine took place over the next 20 years, in laboratories at the Massachusetts General
Hospital, the University of Pennsylvania, and Thomas Jefferson University.

In 1937, Gibbon (21) 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, but they died a few hours later. Gibbon reported at the 1939 meeting of the American Association for Thoracic Surgery that the survival of cats in good condition had been achieved after a period of total CPB. Clarence Crafoord, the widely respected head of thoracic surgery at the Karolinska Institute in Stockholm, commented in response to the report that a virtual pinnacle of success in surgery had been reached. Leo Eleosser, a distinguished San Francisco surgeon, remarked that Gibbon’s work reminded him of the visions of Jules Verne, thought impossible at the time but accomplished somewhat later (22).

Gibbon’s work was interrupted due to his military service during World War II; afterward he resumed his work at 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 Turin in Italy, and Forest Dodrill at Harper Hospital in Detroit, also worked on a heart-lung machine (23).

Clarence Dennis’s first clinic attempt at open-heart surgery was in a 6-year-old girl with end-stage cardiac disease. Her heart was already massive, and her only hope was surgical closure of an atrial septal defect (24). At operation on April 5, 1951, her circulation was supported by a heart-lung machine that Dennis and coworkers had developed. 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 (25).

In August 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. During the operation, the patient developed hypotension and cyanosis (26). He was placed on partial bypass at 1 L/min. Although the mass was resected successfully, the Italian machine was never used for open-heart surgery in humans.

Forest Dodrill and colleagues used the mechanical blood pump they developed with General Motors in a 41-year-old man. General Motors called it the Dodrill-GMR pump—GMR for General Motors Research laboratories, where it was developed. 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 (27). This, the first clinically successful total left-sided heart bypass, was performed on July 3, 1952, and followed from Dodrill’s experimental work with a mechanical pump for univentricular, biventricular, or cardiopulmonary bypass. Dodrill had used their pump with an oxygenator for total heart bypass in animals, but he felt 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 (28). 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. (29) 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.

Between July 1952 and December 1954, Dodrill performed approximately 13 clinical operations on the heart and thoracic aorta using the Dodrill-General Motors machine, with at least five hospital survivors. While he used this machine with an oxygenator in the animal laboratory, he did not start using an oxygenator with the Dodrill-General Motors mechanical heart clinically until early 1955 (30).

Hypothermia was another method to stop and open the heart. In 1950, Bigelow et al. (31) reported on 20 dogs that had been cooled to 20°C, with 15 minutes of circulatory arrest; 11 animals also had a cardiotomy. Only six animals survived after rewarming. Bigelow and colleagues continued to study hypothermia and hibernation and learned that a groundhog could be cooled to a body temperature of 5°C and be revived (32,33). This temperature allowed circulatory arrest with a cardiotomy procedure lasting 2 hours without ill effects (34).

In 1953, F. J. Lewis and M. Taufic (35) 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 on a 5-year-old girl who had closure of her atrial septal defect on September 2, 1952, using a hypothermic technique.

She was anesthetized and the trachea was intubated. She was then wrapped in refrigerated blankets until after a period
of 2 hours and 10 minutes her rectal temperature had fallen to 28°C. At this point, the chest was entered through the bed of the right 5th rib. The cardiac inflow was occluded for a total of 5½ 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; 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.

This was the first successful repair of an atrial septal defect in a human with surface cooling under direct vision. Shortly after, Swan et al. (36) reported successful results in 13 clinical cases using a similar technique. The 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. (37), 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 (38,39,40,41). Results were much improved, and subsequently the technique was applied also for resection of aortic arch aneurysms in adults.

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. Gibbon successfully used this new machine for intercardiac surgery on small dogs and had several longterm 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 (42).

In 1949, Gibbon’s early mortality in dogs was 80%, but it gradually improved (23). The first patient was a 15-monthold girl with severe congestive heart failure. The preoperative diagnosis was atrial septal defect, but at operation, none was found. She died, and a huge patient 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-IMB heart-lung machine. The patient recovered, and several months later, the defect was confirmed closed at cardiac catheterization. This was the first successful clinical case using the heart-lung machine (43). 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 problem 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 (44) remarked.

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 of the 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% mortality.

However, the continued lack of any success in the other centers around the world that were working actively on heart-lung bypass led to 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. Wangenstein asking, “Is our case still on in the morning?” His answer, “Dear Walt, by all means, go ahead.”

Lillehei et al. (12) used their technique at the University of Minnesota to correct a ventricular septal defect (VSD) in a 12-month-old infant on March 26, 1954. The patient had been hospitalized for 10 months for uncontrollable heart failure and pneumonitis. At operation, a 2-cm membranous 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. (45

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