On the History of Extracorporeal Life Support - Univ of WisconsinBetween the years of 1935 and 1954 John Gibbon, Clarence Dennis, and others pursued the development of a mechanical device to take over the function of the heart and lungs to permit surgical operations on the heart and great vessels.The entire project was stimulated by a patient with a lethal pulmonary embolism. Obviously a machine that could be used to permit cardiopulmonary bypass for this problem could be used for cardiac surgery and a variety of other applications. To substitute for the heart Gibbon used a roller pump which remains in general practice today. To substitute for the lung, he devised a system in which anticoagulated blood was directly exposed to oxygen, dripping along the wires of a vertically-mounted metal screen. The approach of direct exposure of blood to oxygen was successful, and subsequently modified by Dennis, Morrow, Cross, DeWall, Rygg, and many others, leading to the single-use, disposable, direct gas interface oxygenators which are widely used today. Lillihei was the first to use extracorporeal circulation for cardiac surgery, establishing cross circulation between a parent and a child with congenital heart disease, using the parent as the heart/lung machine. Gibbon was the first to use the prosthetic heart/lung machine for a cardiac operation, opening the door to the routine application and success of extracorporeal circulation for cardiac surgery.
As experience with extracorporeal circulation developed during the 1950's, it was obvious that the life-supporting technique itself became lethal when used for more than a few hours. Thrombocytopenia, coagulopathy, hemolysis, generalized edema, and deterioration of organ function all occurred, in proportion to the amount of time on cardiopulmonary bypass. The experiments of Lee, Dobelle, and others indicated that the direct exposure of blood to oxygen gas was responsible for this apparent toxicity. These observations prompted the development of an artificial lung in which a gas-permeable membrane was interposed between the blood and the gas phase. Observation of blood in the Kolff artificial kidney, in which the blood was separated from the environment by a cellophane membrane, indicated that venous blood could become oxygenated if a suitable gas permeable membrane were developed. The first successful membrane oxygenator was built by Clowes et al. They used sheets of polyethylene membrane which had a low but definite permeability to oxygen and CO2. By using a very large surface area, a device was built which allowed gas exchange without a direct gas interface, and this hand-made device was used for cardiac surgery in patients in 1956. The development of dimethylpolysiloxane membranes by Kammermeyer in 1957 was a major advance. This unique material allows for the transfer of carbon dioxide and oxygen at rates that were more than ten times faster than those through other plastics. Using this new plastic (called "silicone rubber") Kolobow, Lande, Pierce, and others constructed blood oxygenators which were quite efficient and successful. The development of these early membrane oxygenators demonstrated 1) that it would be possible to conduct prolonged extracorporeal circulation free of gas interfaces, 2) that diffusion of oxygen through blood would be the limiting factor in oxygenator design rather than the materials, and, 3) that blood flow patterns, headers and manifolds, and stagnant areas leading to thrombogenesis would be important considerations in the design of membrane lungs. In the mid 1960's laboratory research began on prolonged extracorporeal circulation in the laboratories of teams that were studying function and improvement of membrane lungs, particularly Kolobow, Pierce, Galletti, Bramson and Hill, Lande and Lillehei, and Drinker and Bartlett.
The diffusion limitation of oxygen through the blood film, and the use of secondary flows to address this problem were studied by Weissman and Mockros, Bartlett and Drinker, and others. With the collaboration of medical industry a series of membrane lungs became available for clinical trials and general usage. Kolobow and Zapol, Bartlett and Drinker and others, demonstrated that extracorporeal circulation of the blood could be carried out for days or weeks without toxicity or hemolysis as long as the direct blood gas contact was avoided. Beginning with Gibbon, all the studies on extracorporeal circulation have been conducted with the use of heparin anticoagulation, using a dose sufficient to produce an infinitely long clotting time. Bartlett and Drinker demonstrated that much lower doses of heparin could be used, producing prolonged but measurable clotting time which minimized bleeding complications. Several groups studied the management and physiology of prolonged extracorporeal circulation in a variety of animal models.
With these modifications in the equipment and technology of cardiopulmonary bypass, it was possible to characterize physiologic and hematologic responses of the normal animal during prolonged extracorporeal circulation. Several investigators demonstrated that extracorporeal circulation for days was possible without causing significant injury to normal animals. Hemodynamics were easy to regulate. Acidosis, capillary permeability, and organ deterioration which often plagued cardiopulmonary bypass in the operating room did not occur. Bleeding was minimal with adequate control of heparin. Hemolysis was negligible. Thrombocytopenia inevitably occurred but was manageable. All of these studies in the animal laboratory showed that the technique was feasible, and provided the background for early clinical trials.
The first attempts at respiratory support in infants were reported by Rashkind, Dorson, and White. The first successful human case was reported by Hill, O'Brien, and others in 1972. The patient was a young man who sustained a ruptured aorta and other injuries in a motorcycle accident in Santa Barbara, California. Don Hill and his team from San Francisco brought the equipment to Santa Barbara, and managed the patient on venoarterial extracorporeal support for 3 days. The timing of Hill's success was important, because it was in the early 1970's that the full concept of intensive care units developed, acute renal failure was being treated with hemodialysis, and acute respiratory failure (ARDS) was the major problem in critically ill patients. It was hoped that a temporary period of life support with extracorporeal circulation would allow the damaged lung to recover, giving great impetus to both laboratory and clinical research on prolonged ECC. Reports of several other successful cases soon followed. In 1974 the Lung Division of the National Heart and Lung Institute proposed a multicenter prospective randomized study of ECMO in adult respiratory failure. This study began in 1975, which was a pivotal year for extracorporeal support.
In 1975 a meeting was held outside of Copenhagen which included most of the researchers on prolonged extracorporeal support. This meeting was hosted by Zapol and Qvist, and the proceedings were reported in a benchmark publication. The plans for the NIH ECMO study were reported and reviewed at that meeting. Four different membrane oxygenators were manufactured and used in 1975, the Kolobow Sci-Med, the LandÈ-Edwards, the Pierce-GE, and the Bramson (The Food and Drug Administration did not become involved with devices until 1976). And the first successful treatment of a newborn infant with ECMO was done in May 1975 and reported at the Copenhagen meeting.
The NIH-sponsored study of ECMO in adult patients was completed in 1979 and reported in 1980. Other related studies of pathology findings and epidemiology of respiratory failure in the study centers were reported. This was the first attempt at a prospective randomized study of a life support technique in which the end point was death. There were many problems with the study: Nine centers were involved, some of which had no prior experience with ECMO before their first study patient. The logistics of consent to the study tended to exclude the best risk and worst risk patients. A nationwide epidemic of influenza pneumonia occurred in 1976, and these patients dominated the trial. Bleeding complications were major, with average blood loss exceeding 2 L/day. Although the purpose of ECMO is lung rest, many of the patients remained on high ventilator settings. The study was planned for 300 patients, but it was terminated after 92 patients were entered because the survival in both control and ECMO group was less than 10% and it seemed unlikely that the results would be any different after 300 patients. The cause of death was related to technical complications in a significant number of patients, but extensive and apparently irreversible fibrosis was uniformly found at autopsy, indicating that the major problem was not the technology but the underlying parenchymal lung disease. As a result of this study clinical research on ECMO in adult patients essentially stopped in 1979. Since that time only occasional cases have been reported in the United States, and the study of extracorporeal support in adults picks up primarily in Europe.
Evolution of the Concept of Extracorporeal CO2 Removal
Luciano Gattinoni worked with Kolobow at the National Institutes of Health, learning the techniques of extracorporeal support in sheep. He returned to Milan Italy with these hypotheses: (1) The purpose of ventilation is to excrete CO2; oxygenation can be achieved by inflation and airway oxygenation alone. (2) Progressive lung injury in adult respiratory distress syndrome is caused in part by ventilator-induced high pressure or overdistension injury of the most normal alveoli. When functional residual capacity is severely decreased, the remaining alveoli can be over-inflated if high tidal volumes are used, leading quickly to alveolar injury and fibrosis. An extracorporeal support system should eliminate the need for high airway pressure and high FiO2, although this was not always done in the NIH-sponsored ECMO study. (3) If the emphasis should be on CO2 removal to eliminate the need for high pressure ventilation, this could be accomplished with venovenous access, using relatively low blood flow and large membrane lung surface area. (4) This system would allow for normal pulmonary blood flow, even if the lung is severely injured with large amounts of transpulmonary shunting. The venoarterial bypass used in the NIH-ECMO study caused decreased pulmonary blood flow which might have contributed to microthrombosis or inhibition of lung healing.
Gattinoni and his colleagues used these principles in venovenous extracorporeal gas exchange in a variety of adult patients selected by the same criteria used for the NIH ECMO study. In 1986 they reported 21 survivors in 43 patients (49%). These results were corroborated by Lennartz and colleagues in Marburg Germany, Falke in Dusseldorf, Bindslev in Stockholm and Todd in Toronto. Similar results were reported by Morioka of Kumamoto, Japan. All of these investigators reported their results at a European communities conference held at Marburg Germany in 1988.
Bartlett, Gazzaniga, and their colleagues at University of California, Irvine treated the first successful neonatal ECMO patient in 1975 (named by the nurses, Esperanza - Hope). This was soon followed by other successful neonatal cases. By 1981 they had treated 45 newborn cases with 25 survivors. The technique for newborn infants was fairly standardized including venoarterial access via the right internal jugular vein and right carotid artery, heparin titration based on whole blood activated clotting times, "lung rest" at low ventilator settings, and recognition of persistent pulmonary hypertension as the primary underlying pathophysiology. In 1979 the first neonatal ECMO seminar was held at University of California, Irvine, , demonstrating the circuit, the technology, and the concept of the ECMO team, and specialists. This led to the development of ECMO research teams at Richmond, Pittsburgh, and Detroit. In 1980 the neonatal ECMO project moved from the University of California, Irvine to the University of Michigan and experience gradually increased from a few cases each year to a few cases each month. Representatives of other centers attended the annual seminar, and some established ECMO teams - all with a standardized system and protocol. By the end of 1986 715 newborn cases had been treated in 18 centers with excellent survival results reported from each center.
With the technique standardized and an experienced team trained, the Michigan group carried out a prospective randomized study in newborn infants between 1982 and 1984. They used a statistical technique called randomized play-the-winner, in which assignment to one treatment or the other is randomized, but influenced by all the previous patients in the study. Statistical significance is reached when there is a significantly larger group of patients in one arm of the study compared to the other. This resulted in the unusual groupings of one control patient (who died) and 11 ECMO patients (all of whom survived). This proved that the results with ECMO were better than conventional therapy, but the study was treated with skepticism. The most articulate of the critics - Ware and Epstein - undertook to design a prospective randomized study of ECMO in neonatal respiratory failure, but soon encountered the same problems of ethics and logistics. They solved this problem by using a similar adaptive statistical design, and reported their prospective randomized study (with similar results) in 1989.
ECLS has been used for cardiac support for three decades, following the initial studies of Dennis, who placed a transseptal catheter into the left atrium via the internal jugular vein and right atrium, and perfused this oxygenated blood into the femoral artery, providing systemic perfusion and unloading the failing left ventricle at the same time. Although successful, this technique was never widely applied, primarily because counterpulsation with an intraaortic balloon was simpler, and provided adequate support for most patients with a failing but recoverable left ventricle. ECLS has been reserved for right ventricular failure or bi-ventricular failure. For these reasons, the technique has been used most extensively in pediatric patients following operations to repair congenital defects. When low cardiac output occurs in these children, it is usually due to right or biventricular failure, and often improves during a few days of ECLS, as the heart adjusts to new hydrodynamics. In recent years the success of cardiac transplantation has renewed interest in extracorporeal circulation as a means of cardiac support, both for supporting the failing transplanted heart temporarily, or serving as a bridge to cardiac transplantation.
In 1996 there are over 100 active centers using extracorporeal support as routine treatment for severe respiratory failure in newborn infants, and an additional 27 centers using extracorporeal support for adult respiratory failure. With more than 10000 newborn cases reported, the overall survival rate is 80%. The most experienced centers report survival consistently greater than 90%. Survival in centers treating adult respiratory failure is remarkably constant at 50%. Similar results are reported for support of older children and support of patients with primary cardiac disease. In 1989 the active ECMO centers joined together to form a Study Group called the Extracorporeal Life Support Organization. The purpose of this group is to maintain the data Registry, conduct clinical studies on extracorporeal support, and serve as the communication center for research and clinical practice on extracorporeal life support.