|HISTORY OF MEDICINE
|Year : 2009 | Volume
| Issue : 2 | Page : 94-101
The magnificent century of cardiothoracic surgery
M.D., Consultant, Cardiothoracic Surgery, Hamad General Hospital, Doha, Qatar
|Date of Web Publication||17-Jun-2010|
M.D., Consultant, Cardiothoracic Surgery, Hamad General Hospital, Doha
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chaikhouni A. The magnificent century of cardiothoracic surgery. Heart Views 2009;10:94-101
Part 5: The Heart-Lung Machine
"It is not in the nature of things for any one man to make a sudden violent discovery. Science goes step by step, and every man depends on the work of his predecessors".
Sir Ernest Rutherford
Probably the single most important device used by cardiac surgeons these days is the cardio-pulmonary bypass machine. The perfusion pump, or the heart-lung machine, is the most important stigma of cardiac surgery … It is the flag ship that distinguishes this surgical field from others, and that is where I will launch my trip.
The two main components of cardio-pulmonary bypass pump are the pump and the oxygenator, and each has a long interesting story to tell. The discovery of Heparin and Protamine, the use of hypothermia, hemodilution and cardioplegia significantly improved safe application of cardio-pulmonary bypass in open heart operations. But first let's go back to the original stimulus behind developing this machine.
| Pulmonary embolectomy|| |
Friedrich Trendelenburg (1844-1924) in Germany was the first surgeon to attempt a pulmonary embolectomy. In his classic paper that appeared in 1908, he stated that the clinical picture is characteristic: "rapid collapse, frequently accompanied by substernal pain that often causes the patient to suddenly scream wildly". He reported on animal studies in 1907; following exposure of the heart, he incised the conus pulmonalis, inserted a cannula, advanced it into the pulmonary artery, and removed emboli using suction. Further experimentation revealed that a direct incision in the artery with removal of the emboli using forceps that was designed to remove polyps was much easier. He described his first unsuccessful pulmonary embolectomy in a human. That operation became famous and is known as the Trendelenburg operation.
Trendelenburg subsequently reported two more cases, both fatal. The first of those two patients died 15 hours postoperatively of cardiac failure, the second 37 hours postoperatively. Kirschner, Trendelenburg's student, reported the first patient who fully recovered after undergoing pulmonary embolectomy in 1924. By 1937, John Gibbon estimated that only 9 of 142 patients who had undergone the Trendelenburg procedure worldwide left the hospital alive. These dismal results were a stimulus for Gibbon to start working on a pump oxygenator that could maintain the circulation during pulmonary embolectomy. A heart-lung machine.
| A story of persistence and stamina|| |
[Additional file 1]On May 6, 1953, the first successful truly open-heart operation was performed with the use of the heart-lung machine. On that spring day in Philadelphia, John Heysham Gibbon (1903-1973) of the Jefferson University Medical Center, using total cardiopulmonary bypass for 26 minutes, closed a large secundum atrial septal defect (ASD) in an 18-year-old woman. Beginning with this case, generations of cardiac surgeons have been able to operate on millions of human hearts.
[Additional file 2] [Additional file 3]The patient had congestive heart failure due to a large ASD, and her cardiac catheterization revealed a large left-to-right shunt at the atrial level. After complete heparinization, the arterial inflow cannula was placed in the left subclavian artery, and the inferior and superior venae cavae were cannulated. All this was done through bilateral submammary incision, the so-called clamshell incision. After opening the atrium, a large secundum ASD was identified, and was closed with a running cotton suture. The patient was removed from the heart-lung machine without incident after approximately 26 minutes. She made an uneventful recovery and was discharged 13 days postoperatively. She was recatheterized 6 months postoperatively, and the defect was found to be completely closed. The case was absolutely astounding to those who witnessed it, as it was to the entire world soon after it was announced in the press.
John Gibbon had studied and worked tirelessly on this project for 23 years before the first successful application. In 1930, he obtained a research fellowship with Edward Churchill (1895-1972) , the Chief of Surgery at the Massachusetts General Hospital (MGH) in Boston. On October 3rd, 1930, Gibbon witnessed the collapse of a patient with a massive pulmonary embolism after a general surgical operation. Gibbon wrote:
"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 [Additional file 4] from the heart. He opened the pulmonary artery and removed massive blood clots. The patient did not survive" .
This dramatic clinical experience had a profound and lasting effect on Gibbon and determined his lifetime academic research interest. He labored at MGH in attempts to develop a machine that can take over the functions of the heart and lungs, allowing surgeons to remove clots from the pulmonary circulation and restore normal circulation.
There was no such machine, but a number of investigators in the early years of the 20th century had been working on isolated animal heart support with oxygenated perfusion, perhaps the most famous being that of Charles Lindbergh working with Alexis Carrel in the 1930s. Even the detail of precisely and consistent anticoagulation was a difficult project in the 1930s, though Jay McLean (1890-1957) had discovered heparin in 1916. Gibbon persisted for 5 years at MGH fabricating pump after pump to support his thesis, and then continued his work in Philadelphia at the University of Pennsylvania in the late 1930s. After World War II, Gibbon became Professor of Surgery at Jefferson. He did his clinical work in the morning and his research work in the surgical laboratories in the afternoon to develop his heart-lung machine. Much of the work was done with his wife, Mary Hopkinson, whose memories were useful in describing the details of this monumental research work.
In the late 1940s, continuing his work on several different versions of the ever-improving heart-lung machine. One of his medical students had been very friendly with Thomas Watson, who was then the Chairman of the Board of IBM. They contacted the IBM Corporation to collaborate on manufacturing the first human version. IBM worked with him in developing Model I of the heart-lung machine. Though relatively successful in extensive experimentation in animals, it was ineffective in supporting cardiopulmonary bypass system in volumes large enough to support a human being. The team had to decipher every aspect of artificial circulation we now take for granted: how to drain the blood from the body, how to pump it back, how to clear air from the inside of the heart, how to get efficient gas exchange, how to anticoagulate successfully without clotting the machinery and how to prevent lethal emboli.
After the first IBM model failed to work well, Gibbon developed a second model in his own laboratory, which was the successful machine that eventually allowed human bypass operations. The final design of Model II developed in the early 1950s consisted of a screen oxygenator, which allowed blood on both sides of the screen mesh to interface with oxygen, and three roller pumps modified from Michael DeBakey's original blood transfusion pump design to pump the blood back into the body. The disassembling, cleansing, and sterilization of non-disposable equipment were, of course, critical and laborious parts of the research project.
Having had increasing success with experimental total cardiopulmonary bypass in dogs, Gibbon was now ready to use this technique in human beings. Gibbon did his first human operation in February 1952, using this machine on a 15-month-old girl with an alleged ASD. At this time, cardiac catheterization was a major event, especially in children, and the patient was too small to have a catheterization before surgery. Unfortunately, this patient died on the operating table because she did not have ASD but rather a left-to-right shunt through a large patent ductus arteriosis.
The second operation he performed with his machine on May 6th, 1953 was the first successful truly open-heart operation performed with the use of a heart-lung machine. Gibbon subsequently operated on 2 additional patients in July 1953, both of whom were young girls about 5 years of age with ASD. These two patients died at surgery with difficulties due to imprecise diagnosis and complications related to bleeding during long time periods on the heart-lung machine. Gibbon, quite upset at these failures, decided to stop using this machine until further improvement. Actually, Gibbon never again did open-heart surgery, leaving his trainees and countless others in the field to carry on. He maintained only a research interest in the development of subsequent models of the heart-lung machine, but it was immediately apparent that others in the field, who were primarily interested in cardiac surgery, such as Clarence Dennis of Downstate University in Brooklyn, [Additional file 5] John Kirklin of the Mayo Clinic, and C. Walton Lillehei at the University of Minnesota, would pick up the challenge, refine Gibbon's original heart-lung machine, and use it extensively. With the improvement of diagnosis and preoperative preparation, uniform anticoagulation, and improved postoperative care, heart surgery blossomed in the late 1950s and early 1960s.
After the development of the heart-lung machine, Gibbon returned to active practice of general thoracic surgery. He became Professor and Chairman of Surgery at Jefferson and was President of the American Surgical Association in 1954 and the American Association of Thoracic Surgery in 1961. He gave his last talk on the development of the heart-lung machine at Baylor University in late 1972 and shortly thereafter passed away in early 1973 at the age of 70 from a fatal heart attack. Despite his monumental work, he did not win a Nobel Prize.
| Was he alone?|| |
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 Digliotti and coworkers at the University of Turino in Italy, and Forest Dodrill at Harper Hospital in Detroit, also worked on a heart-lung machine.
Clarence Dennis's first clinical attempt was in a 6-year-old girl with ASD and advanced congestive heart failure. At operation on April 5, 1951, her circulation was supported by a heart-lung machine that Dennis and his coworkers had developed. The ASD 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 partially 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. The patient was therefore placed on partial bypass for 20 minutes. Although the mass was resected successfully, the Italian machine was never used for open heart surgery.
Forest Dodrill and colleagues used the mechanical blood pump they developed with General Motors on a 41-year-old man. The machine was used to substitute for the left ventricle for 50 minutes while a surgical procedure was carried out to repair the mitral valve; the patient's own lungs were used to oxygenate the blood. This, the first clinically successful total left-sided heart bypass in a human, was performed on July 3, 1952, and followed from Dodrill's experimental work with a mechanical pump for univentricular, biventricular, or cardiopulmonary bypass. Although Dodrill had used the pump with an oxygenator for total heart bypass in animals, they felt that left-sided heart bypass was the most practical method for their first clinical case.
Later, on October 21, 1952, Dodrill used the 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 5 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.
Another major development in open-heart surgery occurred on July 14, 1954, in Stockholm, where Clarence Crafoord successfully removed an atrial myxoma using a disc oxygenator developed by Ake Senning.
John W. Kirklin (1917-2004) and colleagues at the Mayo Clinic launched their open heart program on March 5, 1955. They used a heart-lung machine based on the Gibbon-IBM machine, but with their own modifications. Dr. Kirklin wrote:
"We investigated and visited the groups working intensively with the mechanical pump oxygenators. We visited Dr. Gibbon in his laboratories in Philadelphia, and Dr. Forest 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".
"...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.
...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.... We did our first open heart operation on a Tuesday in March 1955.
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 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" .
By the end of 1956, many university groups around the world had launched open heart programs. Currently, it is estimated that more than one million 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% for some operations. Little thought is given to the courageous pioneers in the 1950s whose monumental contributions made all this possible.
| Oxygenation|| |
Clearly, it is not sufficient for a heart-lung machine to pump blood and deliver adequate blood volume for circulation. The pump must deliver vital oxygen to the tissues and remove carbon dioxide too. It is not enough to function like a heart it also has to function like a lung in gas exchange. Safe and adequate oxygenation was a difficult challenge. The first experimental mixing of venous blood with air as a form of a bubble oxygenator was introduced by Shroder in 1882. Oxygenation across a membrane between blood and air was introduced in 1884 by Gruber. However, safe clinical application had to wait for about 70 years of hard research work and persistence.
Many methods for oxygenating the blood were investigated. Early experiments involved direct injection of oxygen into the blood stream. In the early 1950s, Campbell reported successful cardiac operations in humans using dog lungs, and Mustard reported the use of monkey lungs for oxygenation in human cardiac operations. Lillehei successfully used controlled cross circulation to perform open heart operations. However, these concepts were abandoned because of their difficulty and complexity.
| Film Oxygenators|| |
Gibbon developed a film oxygenator with a rapidly revolving vertical cylinder. The blood forms a thin film on the metal plate where oxygenation took place. The venous and arterial sides of the oxygenator had roller pumps and the blood passed through tubing which was immersed in water bath to maintain a constant temperature. Flows up to 500 ml/min were achieved. He added a wire mesh to produce a turbulent blood-gas interface. This was further improved in the Mayo Clinic pump where they used 14 wire meshes which improved oxygenation efficiency and flow. Also, Kay and Cross developed a rotating disc film oxygenator in Cleveland, however film oxygenators were expensive, difficult to use and required high priming volume, cleaning and sterilization.
| Bubble oxygenators|| |
Initial techniques to simply bubble oxygen into the blood met with disastrous results because of air embolism. Developing micro-bubbles and antifoaming techniques improved the results. The first successful clinical use of a bubble oxygenator was performed on May 13th, 1955 using a design by DeWall and Lillehei in Minnesota to close ventricular septal defect in a three year old child. A reservoir and sponges made of polyurethane and coated with antifoam agent were added by Rygg and Kyvsgaard in Denmark. DeWall introduced a heat exchanger to the bubble oxygenator and put the whole in a disposable pre-sterilized unit which simplified its use.
The venous blood entering the bubble oxygenator unit is passed over a porous plate, through which oxygen is passed, turning the blood into foam of small sized bubbles. Oxygen diffuses across bubble surfaces into the blood, and carbon dioxide diffuses from the blood into the bubbles. The blood is then passed through a de-foaming medium, collects in the arterial reservoir, filtered, heated or cooled and pumped to the patient.
Bubble oxygenators were cheap, efficient and easy to use. They helped many teams around the world to proceed further in performing more complex open heart operations for more than 40 years. However, the foaming-defoaming process caused clinically significant hemolysis after few hours of its use. They also had some risk of micro- and macro- air emboli. The search for better oxygenators was continued.
| Membrane oxygenators|| |
In 1944, [Additional file 6] Willem Johan Kolff (1911-2009) , the famous artificial organs pioneer scientist from the Netherlands, used a cellophane membrane for hemodialysis as an artificial kidney. He later tried to use it as an artificial lung, but found it to be inefficient gas exchanger. Clowes and Neville developed a Teflon membrane oxygenator in 1957, but it was bulky and difficult to sterilize. Bramson developed a new disposable oxygenator using silicon-rubber membrane and included a heat exchanger in 1964. Hollow-fiber membrane oxygenators were proposed in 1963, and were successfully developed by Lillehei team for clinical use by 1967.
In membrane oxygenators, the gas is separated from the blood by a semi-permeable membrane made of polyurethane or silicon-rubber. Gas exchange is accomplished without direct contact between the gas and the blood, just as it is the case in normal lung. In the absence of direct contact between the gas and the blood, extra-corporeal membrane oxygenation (ECMO) can be carried on for weeks without significant hemolysis or organ deterioration. Membrane oxygenators are safe, efficient and easy to use. For these reasons they are now the most commonly used oxygenators.
| Pumping the blood|| |
A variety of mechanical devices were designed and used to achieve efficient and atraumatic blood pumps. Dale and Schuster developed a diaphragm pump in 1928 which used valved inlet and outlet, and Jongbloed used 6 such pumps in parallel to get higher flow in 1949. This concept was used by Lillehei in his early pump operations. Yet, as early as 1934, Michael DeBakey (1908-2008) modified a roller pump for rapid blood transfusion. This concept was used by Gibbon in the first successful open heart operation in 1953. The roller pump works by simple milking of a tube between two diametrically opposed rollers ensuring forward continuous blood flow.
The physiological advantages of pulsatile blood flow were documented in many research reports. However, pulsatile pumps did not become popular because of their complexity, cost and fear of hemolysis. At present, there are two main pump types: positive displacement pumps (such as roller and ventricular pumps), and Kinetic pumps (such as centrifugal or forced vortex pumps). Due to their simplicity and efficiency, roller pumps remain the most common type of pumps used in clinical practice.
| Heparin|| |
One of the essential requirements of the heart-lung machine is anticoagulation. Heparin was discovered by a medical student. The story of discovering heparin is a classical example of what Louis Pasteur, the famous French experimental scientist, said in 1854: "In the field of observation, chance only favors the prepared mind" .
In 1915, Jay McLean (1890-1957) was a medical student working in the laboratory of William Howell (1860-1945) at Johns Hopkins University. McLean took on the project of preparing pure samples of cephalin, a clotting substance obtained from brain tissue. While extracting compounds similar to cephalin from heart and liver tissue, McLean discovered that the liver extract prevented blood from clotting. McLean called the extract heparphosphatid. He wrote:
"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." After McLean left Johns Hopkins, Howell continued working on the liver extract, aided by Emmett Holt (1855-1924). The researchers developed ways to extract an improved water-soluble anticoagulant from liver, which they named heparin in 1918. In the 1920s, animal experiments confirmed that heparin was an effective anticoagulant.
| Protamine|| |
Protamine sulfate is a drug that reverses the anticoagulant effects of heparin by binding to it to form a stable ion pair which does not have anticoagulant activity. The complex of heparin and protamine is then removed and broken down by the reticulo-endothelial system.
[Additional file 7] Johannes Friedrich Miescher (1844-1895) was a Swiss biologist. In the 1870s Miescher discovered a protamine in the sperms of salmon. He also isolated various phosphate-rich chemicals, which he called nuclein (now nucleic acids), from the nuclei of white blood cells in 1869 at the University of Tόbingen in Germany, paving the way for the identification of DNA as the carrier of inheritance. Miescher and his students researched much of the nucleic acid chemistry but their function remained unknown at that time.
Protamine was originally isolated from the sperms of salmon and other species of fish but it is now produced primarily through recombinant biotechnology.
| Filters|| |
When blood contacts the foreign surfaces of the extracorporeal circulation, gaseous and particulate emboli can be generated. In the tubing, the oxygenator, the heat exchanger unit and the suction emboli formation can occur, and if they reach the patient they can cause harm especially to the brain. Actually, placing the patient on cardio-pulmonary bypass pump induces a generalized inflammation reaction which was studied in many centers. The possible neurological complications were recognized very early, and many techniques were developed to minimize it. The use of filters and bubble detectors were very important additional safety measures.
Swank described the presence of micro-aggregates in the reservoir which led him to develop a Dacron filter to remove them. Later studies confirmed less mental confusion when such filters are used, and post-mortem studies revealed fewer brain emboli. More filters were also added in the arterial side of the pump for additional safety.
| Hemodilution and more|| |
In the early days, the oxygenator and the tubings were primed with donor blood, which probably caused some of the features of what was called "post-perfusion syndrome" and "homologous blood syndrome". [Additional file 8] Nazih Zuhdi (1925) , originally from Aleppo, Syria, developed the concept of hemodilution in 1961 by using dextrose solution in the prime. His pioneer work led to the use of clear or crystalloid priming solutions of the cardio-pulmonary bypass circuit. Lillehei confirmed the clinical benefits of hemodiluation in 1962.
Hypothermia had been used in cardiac surgery with inflow occlusion for closure of ASD in 1952 by Lewis and Swan in USA. Sealy at Duke University used a combination of cardiopulmonary bypass and hypothermia for the first time in clinical application for closure of ASD. In 1958, Sealy reported successful use of this technique in 49 operations. The pump was later used for correction of complex congenital cardiac malformations under deep hypothermia and circulatory arrest.
Cardioplegia, Hemofiltration and in-line measurement of blood gases and potassium were later developed to improve the safety of cardio-pulmonary bypass circulation and to give the surgeons more time to concentrate on the accuracy and precision of the operation rather than on speed. The dream that once flashed though the mind of a young surgeon in Boston while observing a dying patient suffering from severe pulmonary emboli finally came true and changed the world of cardiothoracic surgery forever.
| References|| |
|1.||Robert S. Litwak. "The growth of cardiac surgery: Historical notes". Cardiovasc Clin 1971;3:5-50 |
|2.||Richard H. Meade. "A History of Thoracic Surgery"; 1961, Bannerston House. |
|3.||Louis Acierno. "The History of Cardiology: Men, Ideas and Contributions" 1994, Informa Health Care. |
|4.||Stephen Westaby and Cecil Bosher. "Landmarks in Cardiac Surgery". 1998, Informa Health Care. |
|5.||Philip H. Kay and Christopher M. Munsch. "Techniques in Extracorporeal Circulation". 2004, Arnold Publishers. |