Ann Thorac Surg 2009;88:355-361. doi:10.1016/j.athoracsur.2009.04.120
© 2009 The Society of Thoracic Surgeons
Presidential Address
By the Numbers!
John W. Hammon, MD*
Department of Cardiothoracic Surgery, Wake Forest University, School of Medicine, Winston-Salem, North Carolina
* Address correspondence to Dr Hammon, Department of Cardiothoracic Surgery, Wake Forest University, School of Medicine, Winston-Salem, NC 27157 (Email: jhammon{at}wfubmc.edu).
Two things that Dr David Sabiston said during my surgical resident training at Duke have stuck with me. The first he said was that, "when doing research, think of how it will help patients." He only said that to me once (one morning when we were discussing patients), and then he asked about how my research was going. The second, he said many, many times; this expletive, "Numbers Please!" usually occurred on rounds when we would be discussing a clinical case and the resident doing the discussion would give an opinion on the method of treatment or the outcome. Dr Sabiston was intent on residents searching the literature for specific conditions and operations, and quoting that literature rather than giving their own opinion, because we had little experience on which to base our own opinions. This was his contribution to what we now call evidence-based medicine.
When at Duke, and then at Vanderbilt, I had significant experience in research, much of which was basic research that ended up having little clinical application. My clinical research was much more interesting, but frustrating, as much of my time was devoted to clinical practice. In 1958, Francis D. Moore (from Boston) made this statement, which I have paraphrased because it summarized my research career at the time I arrived in Winston-Salem and Wake Forest in 1991: "A surgical investigator is like a bridge tender channeling knowledge from biological science to the patient's bedside. Those at one end of the bridge say he is not a good scientist and at the other not spending enough time in the operating room. If only he is willing to live with this abuse can he continue to do his job well" [1].
Sabiston's statement about research and helping patients has now been implemented into a whole field known as translational research. The United States National Institutes of Health (NIH) has made translational research a priority, forming centers of translational research at its institutes, and launching the clinical and translational and science program in 2006 [2]. The definition of translational research means different things to different people. One group would define it as bench to bedside research, in which basic knowledge is used to formulate a treatment or device, such as a new drug, which is then brought to market. This is an extremely important activity for the business of medicine.
The other definition, which I believe has much more relevance to surgeons, is to ensure that new knowledge and treatments reach appropriate patients and are implemented properly. We must remember that surgeons have a moral and ethical stake in any new treatment they devise. Outcome efficacy for surgical treatment is much more stringent in this day and age than is treatment with drugs or other less dangerous medical therapies. Therefore, translational research, as it relates to surgeons, could be defined as bench to practice.
Despite the fact that the NIH has recognized translational research only since 2006, I would submit that translational research has been a feature of surgery for centuries. According to the history books prior to 1700, surgery was practiced mainly by the executioner and the barber. The most common operation at that time was amputation, and most of these were performed by Army surgeons who were called Feldscherer or field shavers in Germany, because it was their duty to shave the officers when they were not treating sick and injured soldiers [3]. When John Hunter came on the scene, surgery ceased to be regarded as a mere technical mode of treatment and began to take its place as a branch of scientific medicine, firmly grounded in physiology and pathology. When he came to London in 1748, as a raw, uncouth Scottish lad, he was taken by the hand by his more refined brother, William, and he was taught dissection in the cadaver laboratory (Fig 1). He soon found himself teaching anatomy and observing surgery. After an experience as a field surgeon with the British Army, he settled down in London to a life of ardent, original investigation, diversified by extensive surgical practice and teaching. He collected a huge number of specimens from patients and animals that are now displayed in the Hunterian Museum. His greatest innovation was the development of the surgical principle that aneurysms due to arterial disease should be ligated in healthy tissue by a single proximal ligature, a technique he established in 1786. What Hunter did for the poor social status of the surgeon at that time can be illustrated by a remark of one his colleagues: "He alone made us gentlemen" [4].
Now let us fast forward 100 years and go to New Orleans, Louisiana. The treatment for an aneurysm was about to take a dramatic turn. In 1888, a young man with a traumatic brachial artery aneurysm presented to Charity Hospital in New Orleans and was seen by 22-year-old surgeon, Rudolph Matas, who had just organized the New Orleans Poly Clinic. This clinic became the Tulane Medical School, my alma mater. Matas tried all of the standard therapies for this large and growing false aneurysm, which included the following: direct and indirect pressure, ligation of the artery immediately above the tumor, ligation immediately below the tumor, and finally incision and partial excision of the aneurysm sac (later known as endoaneurysmorrhaphy) [5]. This radical departure from the Hunterian principle, once and for all, changed the surgical therapy for arterial aneurysm (Fig 2). By 1900, Matas had a series of more than 600 operations on blood vessels of which 260 were for aneurysms. His knowledge of collateral circulation and the physiology of blood flow gained by extensive dissection of cadavers allowed him to understand the pathologic anatomy of aneurysms and most of his patients received limb-sparing operations as opposed to the Hunterian approach.
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Fig 2. A photograph of Rudolph Matas with his first report of endoaneurysmorraphy. (Reproduced from Matas R, Medical News;1888;53:462–6 [5].)
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Again, fast forward to the mid-1900s in which Michael E. DeBakey had just become the professor and first chairman of the Department of Surgery at Baylor University College of Medicine in Houston. In that day and age, resection and grafting of large and extensive aortic aneurysms was unheard of in the United States, with only a few operations being performed around the world. In 1956, DeBakey and colleagues [6] presented a paper before the Southern Surgical Association in which he described homograft repair for thoracoabdominal aneurysms (Fig 3). His later work (on which his fame is based) was for the development of synthetic vascular grafts and thousands of operations for aneurysms and other forms of cardiac and vascular disease [7]. Thus we have seen the evolution of the treatment for arterial aneurysm during the course of 200+ years by surgeons practicing translational research. A key factor in their success was the surgeon's responsibility for the outcome. The result of this ownership and a thorough knowledge of the physiology of blood flow and cardiovascular function in that era were innovative therapies and better patient care.
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Fig 3. Michael DeBakey with a copy of his ground breaking article on repair of thoracoabdominal aneurysms. (Reproduced from DeBakey ME, Creech O, Morris GC, Ann Surg;1956;144:549–72 [6], with permission from Wolters Kluwer Health.)
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Perhaps the ultimate example of translational research in surgery were the contributions of Joseph E. Murray, a plastic surgeon who studied the effects of skin grafting from identical twin animals and nonrelated animals, which provided one of the first descriptions of transplantation immunity. He used this knowledge and his surgical skill to head a team performing the first kidney transplant in 1954, and subsequently worked with Gertrude Elion in developing immunosuppressive drugs that led to the expansion of living related and cadaver transplantation [8]. He was honored in 1990 as one of the very few surgeons to receive the Nobel Prize in Medicine.
When I came to Wake Forest School of Medicine in 1991, I was very lucky to "fall in" with two wonderful colleagues, Dr David Stump and Dr Dixon Moody; together we formed a neuroprotection research group. At that time, there was a beginning wave of enthusiasm for studying the noncardiac outcomes of cardiac surgery performed on patients with cardiopulmonary bypass. In 1980, John Kirklin, himself, a wonderful translational researcher who was interested in surgical outcomes, spoke at the twenty-fifth anniversary of open heart surgery at the Mayo Clinic. He said, "The physico-chemical changes produced in the formed and unformed elements of the blood by exposure to nonbiological surfaces in the bypass circuit produce profound and widespread functional and biological abnormalities in patients" [9]. He went on to say that solutions to these complex problems would not only be intellectually rewarding and save lives, but would considerably increase the cost effectiveness of cardiac surgery, which has proven to be a central issue in this arena.
At Wake Forest in the 1990s, attention was now turning to other organ systems that may have been impaired during cardiac operations. There was concern that many successful cardiac operations were complicated by stroke, coma, or delirium. An appreciation of atherosclerotic emboli, occurring as a result of manipulation of the aorta during surgery could cause stroke and renal failure. In addition, an inflammatory reaction often developed in patients having cardiac surgery, which was manifested by fever and multisystem organ damage.
The first of my collaborators, Dixon Moody, the head of Neuroradiology at our medical center, had been studying the brains of patients dying of Alzheimer's disease in the 1980s, and trying to correlate changes in the cerebral microcirculation with images on magnetic resonance imaging. At that time, Dr. Jacob Vinten-Johansen (a PhD cardiovascular physiologist working with us in our research laboratories) was performing experiments on dogs with cardiopulmonary bypass. Moody approached Vinten-Johansen and asked if he could donate the brains of these dogs for his studies, as he needed normal brain tissue to compare with diseased specimens. After several weeks, Moody excitedly came back to Johansen showing him pictures of the cerebral microcirculation that illustrated what Moody was calling small capillary arteriolar dilatations, or SCADS. The cause of these abnormalities was not known until Moody performed special stains and found that the dilatated vessels contained fat emboli. Subsequent studies demonstrated that these fat emboli arose from suctioning wound blood (from the pericardial well during cardiac surgery) that contained fat from the sternal marrow and surrounding subcutaneous tissue, which had high levels of triolein. The building block of triolein is oleic acid, which is very toxic to the vascular endothelium. It became obvious that these fat emboli were capable of causing the breakdown of the blood brain barrier in animals that had been given a constant infusion of indocyanine green. This dye stays in the intravascular space unless blood vessel damage has occurred. In that situation, indocyanine green ends up leaking into the interstitial space surrounding a fat embolus in the cerebral circulation. The clinical counterpart to this research phenomenon is cerebral edema.
Additional studies demonstrating upregulation of the inflammatory response surrounding these fat emboli suggested that the delirium and occasional coma in patients, after long cardiac operations in which the cardiotomy suction was used to aspirate large quantities of blood and re-infuse them back into the patient, may be responsible for some of the neural damage manifested in the early postoperative period. Additional long-term studies performed in England showed that patients with this type of neural damage often have permanent brain shrinkage believed to be due to dropout of individual neurons injured by this process [10].
My second collaborator, David Stump, a PhD neuropsychologist, came to our institution in 1988, from Houston, where he had developed a neuropsychological instrument to measure changes in multiple cognitive processes in patients after cardiac surgery. Dr Stump performed preoperative and postoperative neuropsychological studies on patients in our institution and demonstrated that at least 30% of these patients (particularly those older than 70 years of age) had cognitive deficits that were present after surgery [11]. Practically speaking, it meant that 1 of 3 patients had difficulty in doing tasks involving fine motor activity and coordinating the thinking involved with motor activity, such as performing a crossword puzzle. These findings were very worrisome; we were also concerned by the large number of emboli recorded by ultrasound in the carotid arteries of patients having cardiac surgery [12]. These emboli were present in all cardiac operations, particularly coronary artery bypass surgery using techniques that involved manipulating the aorta with multiple clamping. This suggested that plaque material was being dislodged and carried toward the brain.
We therefore formed a clinical research team and set about to design a protocol that would minimize aortic manipulation and avoid re-infusing wound blood into the patient. The members of this team are shown in Figure 4. We also benefited from the sage advice of Dr John Butterworth (now the chair of anesthesia of the University of Indiana School of Medicine) and Dr Bill Brown (a PhD from the neuroradiology department). The final protocol used specific techniques including transesophageal or epiaortic ultrasound scanning of the aorta to localize plaques and to avoid them during cannulation and vein graft insertion. We used a single, cross-clamp application, and we adequately vented the aorta and left ventricle to remove potential embolic material. We used mild hypothermia to protect the brain, and we avoided cardiotomy suction whenever possible. In patients with extremely atherosclerotic aortas, and in patients with unstable cerebrovascular or renal vascular disease, the use of off-pump surgery was preferred. After a successful preliminary study demonstrating that our new techniques had markedly reduced neurocognitive changes after surgery, we performed a randomized, prospective study comparing the modified surgical techniques noted as the single-clamp technique versus the more traditional multi-clamp technique. This research was funded by a grant from the National Institute of Neurological Disease and Stroke; the study was performed between 1999 and 2005. We found that patients who underwent the more traditional multi-clamp technique had a 3.15 times greater probability of a neurologic dysfunction (ie, either stroke or neurocognitive deficits) than patients who were treated with the modified technique [13].
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Fig 4. The Neuroprotection During Cardiac Surgery Group 2007. Front row: Dixon Moody, MD, John Hammon, MD, and David Stump, PhD. Back row: Dwight Deal, BS, Tim Oaks, MD, Kashema Rorie, PhD, Neal Kon, MD, and Ted Kincaid, MD.
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When we re-examined our data and tracked neurocognitive deficits, we found those that appeared at the time of surgery and were then persistent for 6 months were found to be almost universally permanent. We found that the improved technique resulted in only 11% of the patients with a persistent neurocognitive deficit that resulted from surgery [14]; this was compared with a 30% persistent deficit rate in the multiple clamp group, and also in a nonrandomized comparison group of patients with off-pump coronary artery bypass.
We have been very pleased with these results and have noticed marked improvement in a number of outcome measures in our patients, including time to awakening after anesthesia, time in the intensive care unit, total hospital stay, and total hospital expenses. This change in practice is the hallmark of successful translational research with improved patient care as the ultimate goal.
I would also like to recognize the contemporary contributions of two of my colleagues in the Southern Thoracic Surgical Association. Bill Baumgartner and his group at Johns Hopkins University Medical Center have played an instrumental role in neuroprotection research and are following a clinical series of patients demonstrating that long-term follow-up of patients after cardiac surgery does not result in significantly decreased cognitive function when compared with patients who have similar disease but did not have surgery [15]. Hank Edmunds, our editor, has had a longstanding interest in the deleterious effects of cardiopulmonary bypass and has most recently been able to conclusively prove that wound blood reintroduction into the cardiopulmonary bypass circuit is the most powerful causing agent in the postoperative inflammatory reaction [16].
I would also like to recognize several members of The Society of Thoracic Surgeons Association who have done significant translational research. These are men that I know and respect their work, and thus would like to demonstrate that respect by mentioning them in my remarks. I mean no disrespect to others, but this is work that is meaningful to me and the association.
The first is Bill Gay who was my senior in the residency program at Duke, and during his research year he studied myocardial metabolism. He carried this work to Cornell when he joined Paul Ebert at the completion of his residency. He continued his basic research and found that in isolated, perfused hearts a small amount of potassium chloride added to the standard Krebs solution produced a flaccid, quiet heart, which demonstrated better metabolism at the end of a period of normothermic ischemia [16]. This work was published in The Annals of Thoracic Surgery in 1975, as part of the Intraoperative Protection of the Myocardium Symposium held at the NIH (Fig 5). It is also significant that Dr Gay used his cardioplegia, as he named it, on a large patient series and published the results, showing excellent myocardial protection, particularly in the hypertrophied heart. The elements of cardioplegia have been copied and altered numerous times throughout the years, and priority has been claimed by several individuals. However, Gay's article is the first in the literature that I can locate, in which the word cardioplegia is used to describe the use of potassium chloride for myocardial protection.
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Fig 5. Bill Gay and his article describing potassium cardioplegia. (Reprinted from Gay WA, Ann Thorac Surg;1975;20:95–100 [16], with permission.)
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Jim Cox was my co-resident at Duke, and during his residency he did significant research in electrophysiology. Cox studied mechanisms of arrhythmia as they relate to the Wolff Parkinson White Syndrome, and subsequently he identified the very complicated electrophysiologic mechanisms related to atrial fibrillation. After that basic research, he developed an operation that has been shown to have the best results of correction of atrial fibrillation (Fig 6), which was named the Cox maze procedure [17]. When it did not achieve widespread usage because of the length and complexity of the surgery, he had the good sense to develop a minimally invasive approach for this operation and worked with the industry to develop high-frequency ultrasound techniques for producing lesions in the myocardium for electrical isolation. Modifications of his maze procedure are now in use throughout the world on thousands of patients. Time will tell if high-frequency ultrasound will give superior results in either open or closed surgery.
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Fig 6. Jim Cox and his article on the first clinical series of the Maze procedure. (Reprinted from Cox JL, et al, Ann Thorac Surg;1993;56:814–24 [17], with permission.)
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Mike Mack is our president-elect who has distinguished himself by performing careful, clinical research and developing innovative techniques to permit off-pump coronary artery bypass surgery. His use of postoperative cardiac catheterization was the first effort to verify early graft patency and serve as a standard in developing new coronary revascularization procedures [18] (Fig 7). His team has introduced new surgical procedures and techniques to our practice and each has been carefully studied with precise outcome data. He has developed a research institute, which is operated with private funds and has partnered with industry for the development of new devices to aid the surgeon and improve outcomes.
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Fig 7. Michael Mack with the results of his translational research on graft patency comparing off-pump coronary artery bypass surgery to on-pump surgery. (Reprinted from Mack MJ, et al, Ann Thorac Surg;1999;68:383–90 [18], with permission.)
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Probably none of these surgeons, especially myself, will get the Nobel Prize. However, I believe there is a chance that the next person I mention will possibly receive it, and that is, Ranny Chitwood, who has spent the better part of his career in cardiac surgery developing minimally invasive techniques for open surgery. He has been instrumental in the development of endoscopic and robotic mitral valve surgery, and he presented an excellent review of his work at the Lillehei Symposium in 2004, in honor of the great cardiac pioneer, C. Walton Lillehei [19]. Chitwood and his team have performed hundreds of minimally invasive cardiac operations using endoscopic approaches with the aid of three-dimensional imaging followed by robotic procedures (Fig 8). Most surgeons would like to become immortal by having an instrument named after them. Chitwood has achieved that status by first developing a clamp that carries his name and is used for minimally invasive aortic clamping [20], and second, by being inducted in the Royal College of Surgeons as one of the chain of Hopkins—Duke—East Carolina surgeons receiving this honor.
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Fig 8. Ranny Chitwood and his article reviewing his large experience with thoracoscopic and robotic mitral valve surgery. (Reprinted from Chitwood WR Jr, et al, Ann Thorac Surg;1997;63:1477–9 [19], with permission.)
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In summary, surgical translational research is a worthwhile endeavor and results in improved patient care and better surgical outcomes. I am a better man for having persisted through the endless grant submissions to the NIH and the American Heart Association (ie, funds which are harder and harder to obtain, and as a result fewer surgeons have publicly funded grants). Wisely, our societies have begun programs to interest residents and young faculty members in research and grant preparation.
Just as with clinical medicine, research is more tightly regulated, and this regulation is very obvious in university practices. I believe that our research offices and institutional review boards have become small bureaucracies that are more interested in protecting the university than encouraging and facilitating research. For that reason, I believe that great opportunities are present in the private sector for surgeons, partnering with the industry for translational research. It is important that our relationships with the industry are not spoiled by allegations of conflict of interest. Disclosure of relationships and the financial consequences are essential. I do believe that careful study of our patients (now being facilitated by The Society of Thoracic Surgeons' database) will help us to be better doctors. Publishing our clinical series, particularly when based on sound scientific knowledge, will let us practice medicine "by the numbers!"
I would like to leave you with one great piece of advice that I believe is relevant for all surgeons and that has come down through the centuries, as it was written sometime in the 14th century by Leonardo da Vinci, the great renaissance scholar: "Those who fall in love with practice without science are like a sailor who enters a ship without a helm or compass, and who never can be certain whither he is going."
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Acknowledgments
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The author would like to thank Kathy McNoldy for her help in preparation of this article.
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Footnotes
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Presented at the Fifty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Austin, TX, November 5–8, 2008.
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References
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- Moore FD. The university in American surgery Surgery 1958;44:1-10.[Medline]
- Woolf SH. The meaning of translational research and why it matters JAMA 2008;299:211-213.[Free Full Text]
- Garrison FH. An introduction to the history of medicine4th ed.. Philadelphia PA: WB Saunders; 1929341.
- Ibid, 344-8.
- Matas R. Traumatic aneurysm of the left brachial artery Medical News 1888;53:462-466.
- DeBakey ME, Creech OA, Morris GC. Aneurysm of thoracoabdominal aorta involving the celiac, superior mesenteric and renal arteries. Report of four cases treated by resection and hemograft replacement. Ann Surg 1956;144:549-572.[Medline]
- DeBakey ME, Cooley DA, Crawford ES, Morris GC. Clinical application of a new flexible knitted Dacron arterial substitute Am Surg 1958;24:862-869.[Medline]
- Murray JE. Reminiscences on renal transplantationIn: Chatterjee SN, editor. Organ Transplantation. Littleton MA: John Wright, PS, Inc; 1982. pp. 1-13.
- Kirklin JW. Open heart surgery at the Mayo Clinic: The 25th Anniversary Mayo Clinic Proc 1980;55:339-341.[Medline]
- Kohn A. Magnetic resonance imaging registration and quantification of the brain before and after coronary bypass surgery Ann Thorac Surg 2002;73:S363-S365.[Free Full Text]
- Stump DA. Selection and clinical significance of neuropsychological tests Ann Thorac Surg 1995;59:1340-1344.[Abstract/Free Full Text]
- Stump DA, Rogers AT, Hammon JW, et al. Cerebral emboli and cognitive outcome after cardiac surgery J Cardiothorac Anesth 1996;10:1-8.
- Hammon JW, Stump DA, Butterworth JF, et al. Single cross clamp improves 6-month cognitive outcome in high risk coronary bypass patients: the effect of reduced aortic manipulation J Thorac Cardiovasc Surg 2006;131:114-121.[Abstract/Free Full Text]
- Selnes OA, Grega MA, Borowicz LM, et al. Cognitive outcomes three years after coronary bypass surgery: a comparison of on-pump coronary bypass surgery and non-surgical controls Ann Thorac Surg 2005;79:1201-1209.[Abstract/Free Full Text]
- Edmunds Jr LH, Colman RW. Thrombin during cardiopulmonary bypass Ann Thorac Surg 2006;82:2315-2322.[Abstract/Free Full Text]
- Gay WA. Potassium-induced cardioplegia Ann Thorac Surg 1975;20:95-100.[Abstract/Free Full Text]
- Cox JL, Boineau JP, Schuessler RB, Kater KM, Lappas DB. Five-year experience with the maze procedure for atrial fibrillation Ann Thorac Surg 1993;56:814-824.[Abstract/Free Full Text]
- Mack MJ, Magovern JA, Acuff TA, et al. Results of graft patency by immediate angiography in minimally invasive coronary bypass surgery Ann Thorac Surg 1999;68:383-390.[Abstract/Free Full Text]
- Chitwood Jr WR. Current status of endoscopic and robotic mitral valve surgery Ann Thorac Surg 2005;79:S2248-S2253.[Abstract/Free Full Text]
- Chitwood Jr WR, Elbeery JR, Moran JF, et al. Minimally invasive mitral valve repair using transthoracic aortic occlusion Ann Thorac Surg 1997;63:1477-1479.[Abstract/Free Full Text]
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Acknowledgments
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