2011/02/25 by Warren M. Zapol · 1 citation
Neuroscience · Medicine · Arts and Humanities · #Anesthesia and Neurotoxicity Research #Renal function and acid-base balance #Medical History and Innovations
paper · pdf · doi:10.1097/aln.0b013e31820708d7
openalex publication_date 2011/02/25 · openalex created_date 2016/06/24 · openalex updated_date 2026/07/30
FOR someone beginning a career in anesthesiology in 1970, there was no lack of problems to tackle. While the newly developed field of intensive care had proven capable of resolving simpler, easily reversed clinical conditions (e.g. , temporary postoperative ventilatory insufficiency, atelectasis, transient coma), tougher problems—such as hypoxia in the newborn and adult due to acute respiratory distress syndrome, pneumonia, and sepsis—lay at the frontier of our specialty, posing significant challenges. Early on, I determined that, to make headway in these areas, it would be essential to build a multidisciplinary team that could explore the problem, develop and test solutions in the laboratory, and then, if warranted, at the bedside.My introduction to research at the National Institutes of Health (NIH) in 1967 provided ample evidence to me that medical advances were being crafted by groups of scientists—often from widely separated fields, working in teams on tough problems. The days of the solo, Pasteur-like investigator, working in relative isolation to make major advances or shift paradigms, were over. I learned this key lesson from great mentors at their own scientific frontiers working in teams, and I applied it many times throughout my life.My surgical internship on the Harvard Surgical Service at Boston City Hospital, Massachusetts, in 1967 was interrupted by the Vietnam War. When I failed to get a deferment from the draft to complete my residency via the Berry Plan (a national physicians lottery), I interviewed for the Public Health Service.Luckily, I was selected for a research slot in the Laboratory for Technical Development at the National Heart Institute (now the National Heart, Lung, and Blood Institute) in the NIH Clinical Center, Bethesda, Maryland. That fortuitous event gave me my first in-depth research experience in a large multidisciplinary group. The laboratory leader was Robert L. (“Bob”) Bowman, M.D. (1916–1995), a former student of the pioneering anesthesiologist Emery Rovenstine, M.D. (1895–1960).1–3Bob invented a key instrument used in medical research in the 1970s, the Aminco-Bowman spectrophotofluorimeter (Aminco International, Inc., Lake Forest, CA).4He had joined the National Heart Institute soon after its founding in 1950. By 1970, he was a Laboratory Chief at the Clinical Center, an editor of Science and the Review of Scientific Instruments , a successful physician-inventor, and a confirmed believer in the application of technology to diagnostic and therapeutic medicine. His student and coinvestigator, Theodor (“Ted”) Kolobow, M.D. (National Heart Institute, Bethesda, MD), became my teacher for the next 3 yr.Ted was the inventor of a soup can–sized artificial lung.5He joined the laboratory at NIH after his medical residency. When I met him in 1967, three decades before low tidal volume ventilation was proven beneficial for treating acute lung disease,6Ted was convinced that mechanical ventilation was harmful to the acutely injured lung. He spent much of his effort developing artificial lungs in order to take the weight of gas transport off the injured natural lung so as to enable “lung rest.” Ted was (and is) brilliant and innovative, with an extraordinary knowledge on the frontiers of plastics and polymers. He loved to fashion new kinds of tools for our research. He used his hands in our NIH workshop to craft novel membranes, catheters, and biocompatible surfaces.I would like to share just one example. When we were faced with designing and making thin-walled, nonkinking catheters to drain aortic blood via the umbilical arteries of a sheep fetus (to develop and test an artificial placenta), Ted believed that stainless steel–reinforced polyurethane would be the ideal material for the catheter.7E.I. du Pont de Nemours and Company (Wilmington, DE), which made Lycra®, stated they would have no part in providing the elastomer for our medical catheter. So, Ted dissolved a brassiere made from Lycra (taken surreptitiously from his home) and recast its polymer—reinforced with stainless steel wire—as a fetal umbilical catheter. It worked perfectly.Perhaps most importantly for his young student, however, Ted was a true gentleman teacher. He never raised his voice, was accepting of a novice's mistakes, and often let me learn by making errors and correcting the mistakes myself. He rarely spoke at meetings unless asked. “Don't speak, publish” was his frequent counsel. Ted's influence on my nascent research career was pivotal.With the small hand-made, disposable, artificial lung at our disposal (0.2 M2surface area), the first problem that we set our sights on solving was infant respiratory distress syndrome. We chose a sheep fetus as the experimental subject because their birth weight (2.5–3.5 kg) is similar to that of newborn humans.Few had explored this frontier before us—and none with the tools we possessed. All the members of the NHI team I organized turned out to be essential to our eventual success in isolated fetal perfusion.8Ted led device development; he designed and hand-constructed membrane lungs from silicone rubber membranes cast for us at Dow Corning Corporation (Midland, MI). He also built a special nonocclusive blood pump head (to avoid blood damage),9as well as the vital nonkinking thin-walled and flexible catheters. We recruited Gerald G. Vurek, PhD (NIH Clinical Center, Bethesda, MD),10a bioengineer who designed a flow-thru oximeter for us; Joseph Pierce, DVM (NIH Clinical Center, Bethesda, MD), the NHI veterinarian who orchestrated our dated-pregnancy sheep and carried out the caesarian sections; and John L. Doppman, MD (1928–2000), Chief of Clinical Center Radiology, who helped us angiograph the circulation of fetuses supported on the artificial placenta—a study always performed late at night after patients had gone home (fig. 1).11My first oral presentation at a scientific meeting was on the artificial placenta. It took place at the American Pediatric Society in Atlantic City, New Jersey. I had prepared carefully for the presentation, producing (with the assistance of the NIH Photography Branch) a 16-mm movie of isolated lamb perfusion in a tank of artificial amniotic fluid. I entered the hall early to see if the movie was ready. Aghast, I saw 1,000 people gathered for the plenary session. Fear overcame me. My devoted wife, Nikki—ever the cool-headed one in an emergency—escorted me across the street to a bar for a double gin and tonic. Courage returned. Somehow, I made it through what seemed to be a successful presentation, complete with the movie.The New York Times and Life Magazine made appointments to follow the story. We wrote up our findings and published them in Science .8Clearly, the world was ready for and fascinated by the possibility of using an artificial placenta to carry premature babies to term. Although that goal remains unrealized, after another three decades of advances by our group and many others,12,13extracorporeal membrane lung perfusion of infants with the spiral coil artificial lung of Kolobow became a successful treatment for hypoxia of the newborn.Another dream that we had was to use Ted's artificial lung to help adults with acute lung injury. “Buying time with artificial lungs,” as Nikki poetically phrased it for the New England Journal of Medicine .14This effort required another team of collaborators.Although we performed the first perfusions with extracorporeal membrane oxygenation (ECMO) for adult respiratory distress syndrome (ARDS, as it was then known) at NIH, and for children with infant respiratory distress syndrome at the University of Puerto Rico (Río Piedras) and at Children's National Medical Center (Washington, D.C.), I became convinced that, for me, leaving the sheltered halls of NIH for full-time clinical training would be necessary. I wanted to be certain ECMO was a better treatment for acute respiratory distress syndrome than standard mechanical ventilation. Ralph A. Epstein, MD, then an anesthesiologist at the NIH Clinical Center (later Chief of Anesthesiology, University of Connecticut, Farmington), steered me toward a residency in anesthesiology and an interview with Richard J. (“Dick”) Kitz, M.D., who had just been selected to follow Henry “Harry” K. Beecher, MD (1904–1976) as Chief of Anesthesia at Massachusetts General Hospital (MGH) in 1969.My interview with Dick was the clincher. He assured me of his support for my career as a clinical investigator; introduced me to Henning Pontoppidan, M.D., and Myron B. (“Mike”) Laver, M.D. (1926–1982), who were on the frontiers of mechanical ventilation and oxygen transport, respectively; and suggested that I write an R01 grant titled “ECMO for Acute Respiratory Failure” with Dick as the primary investigator.The grant was to be an initial test of ECMO in the laboratory and on ARDS patients. Dick then fashioned a way for me to continue my life at the frontiers of respiratory research while completing my residency. It was an offer I could not refuse. He suggested as our coinvestigators W. Gerald (“Jerry”) Austen, M.D., and Mortimer (“Mort”) Buckley, M.D. (1932–2007), MGH chiefs of surgery and cardiac surgery, respectively. We also had Henning and Mike as respiratory and cardiovascular coinvestigators. Realizing that I was going to be the one to do the long and grueling initial large animal and human perfusions, Dick kindly offered me a slightly longer anesthesiology residency (then 24 months) with each Friday reserved for ECMO perfusions in large animals (cows and sheep), and time off from the residency for human ECMO trials, which might last, as we later learned, up to 3 weeks (fig. 2).Exploration of the human ECMO frontier at MGH lasted more than 8 yr, well beyond my residency. The work led to a national, multicenter prospective and randomized trial of the technique.15At the start, we had to build a team and learn the basics of ECMO. Which way should we hook up the ECMO device to the patient? Arteriovenous (draining blood from an artery and returning to a vein like the fetal perfusion), venoarterial (like cardiopulmonary bypass), or venovenous (draining from a vein and returning to a more central vein)? The answer wasn't obvious when we began, and only slowly over several years did we learn that venovenous was the preferred in respiratory because it did not cardiac much was Which might to ECMO long should ECMO be to the natural lung while ECMO The of was long and to and in respiratory and cardiovascular we were joined by anesthesiology M.D., who on and helped us the of and Robert M.D., who the of recruited M.D., from at to help us the frontiers of that was the of we recruited Robert L. M.D. a at MGH who was the of and of respiratory the of by J. was also then at MGH (later Chief of Anesthesiology, the pioneering of MGH led to use of to our of its of the to our in many in my by making like get a from a with an of the He also us in our of a long ECMO we were to the life of an with an and amniotic me what I or 8 He me in the and never the of of the in a led me to a of this was our for the of our young led us to a of on the acutely injured circulation and its on the required our team to the M.D., newly recruited from the to Children's Hospital Boston as of was a by helped us cast and the major of the human lung in also recruited M.D., a at to the circulation of ARDS patients in their intensive care with a by using their a he and of our the basics of and the circulation and we for a as an Center of in ARDS laboratory, our clinical on and our on ARDS the from and to our ECMO was the patients young and often by and our was M.D., of and were research by they took the to with developed the intensive care in ECMO. organized and a research meeting on ECMO at in meeting and the that ECMO research on the of frontiers to be days and weeks on we would often of of respiratory research. the most and was the to hypoxia by and I a of a at the American for the of Science meeting in It research by Gerald of University of on and L. of then of University of on the The is large and to in the off The in and a to its blood and from the human with of being to our did this and had they of this knowledge be used in treating human respiratory at the National Science was and of our and he us to to in to the research. my was also and our and and our to the this dream of would have I his support as So, with his (and we to via and spent a on the at from the was a on the of an with and by and of them as with and (fig. this and isolated in at (and to to we had to learn to work on was beginning to and up in and in the to the only with home were via as from our in a of supported by from the National Science which us to our of I a group of to explore this frontier of and of University of was the of the and joined our and at with his and M.D., of New joined us to explore the of fetal the of the became a of the Society of for the of and was after being for his of the of of the of the premature lung and first to its in and on and respiratory gas in respectively. was our anesthesiologist and he organized and provided and most at the beginning of the in I recruited a and who was then a circulation research in my MGH laboratory, to take on a most and and a that was capable of (e.g. , and a pump to blood while for the was and always an on the at a of its we had to it by a with a over its of our team from this Although the were on the we were had to a on the to trial on of us the to the that would experience a when the what this human was and with a off and on a with to a is not a problem in most an in at in a to a is an a designed a special He one of our standard by off the at the and it with for his next field the on his long and He with the his while his the the fetal of our gave this a de as it became that throughout Although had made more with his by the working on the he had worked out that, by vein blood from the and he could in the laboratory at We the of on the selected was a then to our isolated it was with a by a with a a and a The was soon ready for its We by it to the It was capable of several of blood at and times from a The was to the from an isolated that we the We the when the to our to while via a to the field laboratory (fig. that there was a that there was no as a the by and that first had been in animals and and as of by the were that of were the of and in and that, in the did not would be the test of the because it would be on and in their natural the of field we set on the worked at the of each the in at to at the for the of the the at the was more we were to several blood each made that, on each the to a often than that from gas from the was capable of of hypoxia on that would a or human to was with our of the University of New to blood with an the was to the of the blood as the and the (fig. He that blood in the blood times at the to of the blood and made in a field on the confirmed the that the lung on each of the of from gas the The lung then like the lung of a more we an of in the blood on at the of the the blood with dissolved after each us an of so to developing the when their by of our were made by M.D. and of Anesthesiology, University of who used to before and after (fig. He the to the a in the and a its the to take up oxygen while it at the a of our scientific to M.D., then a Harvard medical student and of the built and a oximeter to the of of the of and for the of and is the that the slowly long than He determined that the oxygen by the slowly then a at Massachusetts Institute of set up our field laboratory for that and as a laboratory He did well up our field at the of from our a in the of our field work I to that wasn't always when we his was on a did he a on this I is part of as a young was our first was a in and the of the first to on the of (fig. in my with the as well as my have me in to for the Harvard of I was to learn that a in had been after me by the on (fig. The in my for our research team and its many there was of to be to the to help us human in the MGH intensive care these many and gave us great for to our our work with would the of newborn respiratory By I had circulation for and I was convinced that the of adults with to be to hypoxia and to do it a M.D., and I had with of (later as a and and in the of the ARDS lung and oxygen to artery were by the hypoxia these I was also by an early research study a with artery was with a new the was artery was also and a cardiac physicians were to That experience me that of is a way to artery and it me to another to lung producing there was great when a and was determined to be the of it was learned that was by and was a of and was the key and by and a that in led to the in Medicine being to J. Robert and M.D., I was fascinated by this extraordinary gas and laboratory with my M.D., of the Institute, (now of was at that time to be a and to which then dissolved in producing had been by gas with by first sheep gas and with the laboratory to avoid the that low of could producing in an lamb (fig. The of was of the and the was were and I a team to learn if it was and what respiratory it could be used to or team of M.D., who had just the MGH Chief and was also a the of in fetal then human infants with hypoxia and of the M.D., a anesthesiologist (now of and University of joined in the of the also children with that their were also by M.D., of MGH (now of at was introduced to me in by my Nikki who was then working in the MGH of had the of the for had his in with us in the of the of with in and injured He was to the of the the for in lung fetal well as of the of We learned that is in large by the lung when We were to there was an (a of across the lung when me, this was the beginning of a long and and scientific with that led us much in to our research M.D., to the MGH residency by M.D. of joined me as a the of by and their by like M.D., a from worked with and the of in ARDS working with M.D. (now Chief of Anesthesiology, also in ARDS patients in published their that the injured lung and the of blood through the ARDS this only to the of our team a of 3 yr, the scientific world had from as a to it as a therapeutic gas with and a therapeutic that be used to our clinical of as well as the of many led to several successful randomized of for children with of the newborn as well as of respiratory of the that led to a of the use of as well as an in of these led to by the and in for the use of to at with respiratory the use of with children and adult patients with the each in the primary in infants with of the newborn and respiratory it is widely used and after cardiac surgery in children on the pioneering of M.D., and his at Children's Hospital well as device in this we that a of have been with for is that there as is a therapeutic is the of medical The days of a inventor making a that clinical medical over. therapeutic as a group of medical and their work with a group of laboratory The group and and the laboratory and clinical it the toward to an took the and of of of by The MGH of great for its in to our had to be K. been the on this working for decades on the gas which we to is for scientific advances for experience with and in the MGH effort us and work out we were to to the of babies by a to by the and at (then a of the and at (then a gas the Corporation and became of which later its to New from a laboratory to a the team effort that I success on each his or of our team I that is I this story. it is also to that of our have not to so many research never to on of of in clinical the the treatment of the of lung in premature and the of after research group with M.D., physicians and and an of our team in of the MGH and its a place in the of another an in medical of our team is working on which is when by of or when as an artificial in part as a of its of Although I that there never be a at our laboratory team members that, one in the another invented and in the of this the of I my to and take of the of in making to and medicine. I that so is a of a most life at own is to the of M.D., of and University of New of the research He was an and