- Email: [email protected]
A Three and One-Half Decade Nutritional and Metabolic Iliad
A Three and One-Half Decade Nutritional and Metabolic Iliad Stanley J Dudrick, MD, FACS The intent and purpose of this presentation is to salute and honor an esteemed and cherished friend, Murray F Brennan, MD, for his countless extraordinary contributions to a broad spectrum of the discipline of surgery, but especially to the field of surgical nutrition and metabolism; and also to celebrate concomitantly the multiple accomplishments and influences of his, my, and our, surgical colleagues (many of whom are here with us today), whose relentless and dedicated efforts have contributed collectively to providing impact, potency, and relevancy to the evolution and clinical maturation of total parenteral nutrition (TPN), which has significantly changed the practice of surgery during our professional lifetimes. For three and a half decades beginning in the early 1970s, Murray Brennan has continually maintained an avid interest in surgical nutrition and metabolism and has conducted a productive series of basic and clinical studies in this vital area, resulting in approximately 300 publications of his total of 1,000. His contributions have added significantly to the vast body of knowledge required to attempt to understand and master the nuances and complexities of surgical nutrition and metabolism, and to manipulate parenteral and/or enteral nutrient substrates in a skillful, safe, and practical manner for the benefit of critically ill and complex surgical patients. The concept of feeding patients parenterally by injecting nutrient substances or fluids subcutaneously, or even infusing them directly intravenously, is neither a novel nor a recent idea; it was advocated and attempted long before its successful achievement almost four decades ago. The realization of this seemingly fanciful dream occurred only after more than three centuries of fundamental inquiry, investigation, and discovery, coupled with countless technologic developments and judicious applications of the tediously acquired fundamental knowledge, skill, experience, techniques, and technology. The prerequisites to rational clinical studies in this challenging but vital area included
knowledge of the anatomy and physiology of the circulation; knowledge of the basic biochemical nature of nutrient substrates; knowledge of the interrelationships of these substrates with microbiology, immunology, asepsis and antisepsis; and some knowledge of the complex interactions of food substances with metabolic process, pharmacologic agents, and pathophysiologic conditions. Although various rudimentary, and generally ineffective forms of parenteral nutrition had been attempted clinically sporadically dating back to the early 1900s,1 focused interest and concerted efforts to advance this mode of therapy were heightened and catalyzed in the fourth decade of the last century.2 Robert Elman performed a series of original basic and clinical intravenous feeding experiments and was instrumental in developing intravenous protein hydrolysate substrate solutions that presumably would have led him to the development of a safe and reliable technique of TPN. His investigative work was interrupted abruptly by events related to World War II, in which our Nation’s priorities were shifted dramatically and drastically away from basic scientific medical endeavors to practical wartime efforts. After his return from the war, Elman3 compiled his efforts in a classic tome entitled, “Parenteral Alimentation in Surgery with Special Reference to Proteins and Amino Acids,” and this monograph which was awarded the quinquennial Samuel D Gross Prize of the Philadelphia Academy of Surgery in 1945, was published in 1947. By 1950, the first reports of an effective fat emulsion for intravenous use were published,4 and it became evident that synthetic requirements for protein synthesis and anabolism included the simultaneous administration of adequate caloric substrate to inhibit or minimize the use of administered amino acids for gluconeogenesis, and to provide the energy requirements for peptide bond formation.5 Although most clinicians in the 1950s were aware of the negative impact of malnutrition on morbidity, mortality, and outcomes, apparently only a relatively small percentage of practicing physicians and surgeons understood or expressed the advisability, indeed the necessity, for providing optimal nutritional support for their malnourished patients if optimal clinical results were to be obtained. By 1960, there was demonstration that during caloric starvation, an inevitable loss of nitrogen and a subsequent reduction in total body protein occurred.6 By 1965, it became clear that a complex endocrine interrelationship
Competing Interests Declared: None. Received June 12, 2007; Accepted June 13, 2007. From the Department of Surgery, Yale University School of Medicine, Program in Surgery, Saint Mary’s Hospital/Yale Affiliate, Waterbury, Connecticut. Correspondence address: Stanley J Drudrick, MD, FACS, Saint Mary’s Hospital, Department of Surgery, 56 Franklin St, Waterbury, CT 06706. email: [email protected]
© 2007 by the American College of Surgeons Published by Elsevier Inc.
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governs the use of body fuels, and that this endocrine mediated balance is upset after injury so as to favor endogenous fat mobilization, amino acid release from muscle, and gluconeogenesis.7 But the prevailing dogma during the 1960s was that feeding entirely by vein was impossible; even if it were possible, it would be impractical; even if it were practical, it would be unaffordable. Total parenteral nutrition was considered a “Holy Grail” or “Gordian Knot” pursuit by most physicians and surgeons of that time. This formed a rather intractable wall of ignorance, prejudice, and indifference that had to be penetrated first by developing all of the substrates in forms compatible for delivery to seriously ill patients to provide adequate nourishment intravenously. Second, by demonstrating in the experimental laboratory that such a solution, together with an appropriate, safe, and effective delivery system could provide all essential nutrients in quality and quantity sufficient to support animals for long periods of time. And third, if the animal experiments were successful, applying the techniques and technology to safe, effective, practical use in human beings. I had absolutely no doubt that it would be possible to provide all required nutrient substrates to support cellular metabolism entirely primarily by vein because it is obvious that the vascular circulation is the route by which the body cell mass ultimately receives nutrients. Secondly, my simplified concept of the gastrointestinal tract is essentially that it is a hollow tube that extends from the mouth to the anus and consists of a specialized lining of endothelial cells, together with the attached salivary glands, hepatobiliary system and pancreas, which digest and modify the food substances ingested into the alimentary tract, preparing them suitably for absorption into the portal and lymphatic systems for assimilation into the body cell mass for energy, synthesis, and other physiologic functions. Accordingly, the fundamental problem was to provide all nutrient substances required by the body in forms that could be infused directly into the peripheral blood stream for distribution to all cells and tissues without the necessity of passage initially through the gastrointestinal tract. In the process of attempting to emulate the complex physiology of the gastrointestinal tract in order to bypass its digestive and absorptive functions successfully and effectively by the infusion of all required nutrient substrates intravenously, I gained a great deal of respect for this remarkable multifunctional, multi-organ system. Indeed, I began to tout a cardinal axiom to my students, house officers, colleagues and others that, “The dumbest gastrointestinal tract is smarter than the smartest physician, surgeon, nurse, dietitian, pharmacist, scientist, or nutritionist. This is the inherent fundamental advantage of oral or enteral nutrition over TPN in
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regulating the safety and efficacy of clinical nutritional support.” The most valuable relevant publication available at that time was the monumental summation of the field by Robert P. Geyer,8 entitled “Parenteral Nutrition” and published in Physiological Reviews by the American Physiological Society in January, 1960. It is a 37 page masterpiece citing 659 references; it is the most comprehensive review of published works on parenteral nutrition to that date; and it served as a classic summary and compilation of the most important scientific contributions forming the database upon which ultimately the achievement of TPN was built. Many of the surgical teams that contributed to the early advancement of the original TPN experiences continued, renewed, and intensified their investigative activities in our mutual quest to perfect total intravenous feeding techniques, especially those in Boston, New York, New Haven, and Washington, DC, where many of our contemporary surgical colleagues were actively involved in their training or early academic careers. During the 1970s, in this exciting decade of continuous discovery, modulation of and practical applications for TPN technology and techniques, virtually every Department of Surgery in the country made valuable contributions to the knowledge, experience, and judgment that advanced this important area of endeavor. Several factors account for the persistent and continual stimulation of surgeons and their coworkers to maintain, improve, or optimize the nutritional status of surgery patients under all conditions at all times. The primary impetus for their attention to nutritional status is that surgeons observed throughout the years that operative results, including the rate and quality of wound healing, incidence of complications, and morbidity and survival, were usually best when patients were in good nutritional condition and worst when patients were in poor nutritional condition. A basic etiologic problem is that surgery patients often present with disorders that have impaired their ability to maintain adequate nutrition for some time prior to operation, and/or have impaired or obviated the likelihood, or even the possibility, of obtaining optimal nourishment by conventional alimentary tract routes following operation. Compounding the situation, the primary pathophysiologic condition necessitating the surgical operation, eg, multiple trauma, major burn, extensive neoplasm, often increases the metabolic expenditure of the body’s available calories, protein, and other intermediate substrates for energy and repair, thereby increasing nutrient requirements for homeostasis, recovery, convalescence, and rehabilitation above normal. If the surgery patient is an infant or child, the accentuated nutrient needs for fueling concomitant growth and development introduce a unique pediatric nutritional support problem, further compounding
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the requirements for maintaining metabolic equilibrium throughout the period of surgical diagnosis and treatment. Another nutritional problem indigenous to the practice of surgery is that operative procedures not only inevitably induce or compound existing catabolism, but often temporarily, and sometimes permanently, interfere with the normal digestion, absorption, and assimilation processes at a time when nutritional requirements are usually already increased. The prime example of this situation is massive resection of the small intestine for life-saving indications, resulting in long standing or permanent short bowel syndrome. Finally, the many complicating factors that can occur after major operations, general anesthesia, and major injury secondary to burns or other trauma, such as pneumonia, peritonitis, anastomotic disruption, prolonged ileus, bowel obstruction, enterocutaneous fistula, wound infection or dehiscence, sepsis, shock, and multiple organ failure, can severely aggravate metabolic processes and interfere with restoring normal nutritional status and cellular physiologic function.9 These clinical challenges formed the stimulation and inspiration to develop more effective parenteral means for providing the accentuated nutritional requirements of critically ill patients. Before embarking on this daunting undertaking in the 1960s, we had to identify and assess the prerequisites essential to the development of safe and effective TPN, which included the following:
lutions. This essential requirement for TPN to be successful was contrary to clinical practice standards at the time. It was necessary to concentrate the nutrients required into the volume of water that could be safely metabolized daily in an ill, malnourished patient, and to infuse the mixture at a constant rate over the 24 hours in order to achieve maximum utilization of the accentuated nutrient requirements. ● Maintain asepsis and antisepsis throughout the entire process of solution preparation and delivery. The meticulous and conscientious principles and practices related to sepsis-free TPN solution formulation and infusion, and the compulsive protection and monitoring of the central venous catheter exit site required an extensive re-education program and a major clinical culture change among all healthcare personnel, especially those with the responsibility for attending critically ill surgical patients. ● Anticipate, avoid, and correct metabolic imbalances or derangements. The biochemically and nutritionally active components of TPN solution, coupled with the metabolic consequences and aberrations of a variety of pathophysiologic complications, represented a monumental, unprecedented and unpredictable challenge and undertaking if patient safety was to be preserved during the integration of intravenous nutritional support with treatment of the primary disorder.9
●
Accordingly, the protocol for the development of the essential components of TPN consisted of attempting to achieve the following goals:
Formulate complete parenteral nutrient solutions. Commercially available, medically approved intravenous nutrient substrates did not exist for formulation of nutritionally complete parenteral solutions. So it was not possible to concoct solutions for TPN until all of the components and their mutual compatibility could be determined in our laboratories. ● Concentrate substrate components to hypertonicity (5–6 times isotonicity) without precipitation. This absolutely essential goal was not easily accomplished and required a long, tedious, challenging, and at times, frustrating trial and error process. ● Demonstrate the utility and safety of longterm central venous catheterization. At that time this avenue for percutaneous central venous access was not consistent with standards of care or established safe clinical practices; it was foreign and intimidating to most physicians and surgeons, considered high risk and potentially dangerous, and was not looked on with favor by the medical and surgical hierarchy at that time. Indeed, in many institutions, central venous catheterization was actively resisted or even forbidden. ● Demonstrate efficacy and safety of longterm continuous central venous infusion of hypertonic nutrient so-
● ● ● ●
● ●
Formulate all required intravenous nutrient substrates Devise sterilization procedures and maintain longterm infusion sterility Design and develop practical percutaneous central venous catheters Develop safe longterm central venous catheterization and continuous infusion techniques, principles, and practices Design safe, durable, reliable, versatile infusion pumps and apparatus Establish metabolic compatibility of TPN components with overall clinical goals and with the pathophysiologic conditions.9
Four decades ago the knowledge, experience, techniques, and technologic constituents of the first longterm TPN system were developed in the basic biochemical and animal laboratories, initially in six intravenously fed Beagle puppies, and, subsequently adapted clinically for the efficacious longterm intravenous support of six critically ill adult surgical patients and a newborn infant before its
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widespread clinical application. The details of the orderly and logical scientific development of the principles and components of the techniques in animals, human infants and adults, together with the related indications, limitations, hindrances, complications, motivational factors, clinical applications, and other special aspects, have been described in some detail and reviewed recently.9-13 The remainder of this manuscript consists of a brief outline and an abridged discussion of some of the legacies of the development and successful clinical application of TPN, as follows: The first demonstration that all nutrients required for normal growth and development in animals (initially in Beagle puppies, and later in other species) could be provided longterm entirely by vein safely and effectively. The first demonstration that all nutrients required for normal growth and development in human beings (initially in a term newborn infant, and later in premature infants and older infants and children) could be provided longterm entirely by vein safely and effectively. The first demonstration that positive nitrogen balance, weight gain, wound healing, reduced morbidity and mortality, improved mental and physical activity, and many other desirable clinical outcomes, could be accomplished longterm in critically ill patients nourished entirely intravenously for as long as indicated or required clinically, or for as long as humanely, economically, morally, and ethically justifiable. The development of a wide variety of compatible, complementary and effective (even potentially synergistic) parenteral macronutrient and micronutrient substrates for standard nutritional support, and for special nutritional and metabolic support of seriously ill patients of all ages with a myriad of conditions with or without complications and collateral factors. Formulation of complete crystalline amino acid solutions, fat and water soluble vitamin mixtures, and trace element solutions (previously non-existent) were developed as essential components of an ostensibly complete intravenous nutrition regimen. The development of safe, effective, practical infusion catheters and insertion devices for percutaneous central venous longterm catheterization and indwelling longevity, together with safe and effective insertion techniques and longterm, sepsis-free, safe and effective maintenance techniques, principles, practices, standards, and technology. Furthermore, the introduction of povidone iodine ointment and occlusive waterproof dressings in the management of the indwelling catheter exit site added greatly to the safety and longevity of longterm central venous catheter placement.
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Development of central venous access and infusion techniques and technology for safe and effective longterm administration of nutritional support solutions, resuscitation fluids and electrolytes, blood products and derivatives, and pharmacotherapy. Percutaneous subclavian and jugular vein catheters, implanted multilumen silicone rubber catheters, reservoir port-catheter devices, PICC lines, and multiple modifications and variations were invented to fulfill perceived needs and to provide viable options for longterm central venous infusion. The stimulation and advancement of the technologic revolution in the development of a variety of infusion pumps for longterm ambulatory administration of nutritional formulations, together with appropriate alarms (infusion complete, air-in-line, fluid infiltration or occlusion, voltage drop, power failure or surge, etc.), other safety features, DC battery back-up for AC power, servomechanisms, miniaturization, portability, precision, dependability, etc. The stimulation of the development and advancement of plastic intravenous fluid bags, reservoirs, infusion tubing, administration apparatus, etc., tailored to specific individual patient requirements, situations, and infusates. Plastic bags and containers originally designed for blood products required modification of the plasticizers and plastics for compatibility with, and longterm tolerance of, the more chemically active TPN components to avoid leaching of plasticizers, plastic microemboli and other toxicity. On the other hand, the use of plastic bags for TPN solutions significantly reduced risks of solution contamination, air embolism, and breakage accidents related to glass containers. The stimulation of technologic advances in pharmacy practices with automated, computerized formulation, preparation and admixture apparatus, filtered laminar air flow work areas, cold sterilization of nutrient components and mixtures by membrane filtration, identification of nutrient:nutrient and nutrient: medication interactions and compatibilities, storage principles (refrigeration, preservation, lyophilization), shelf life of solutions, etc. The advancement of the specialty of clinical pharmacology and stimulation of the development of the specialty of nutrition support among pharmacists; the genesis of specially trained parenteral nutrition solution preparation technicians in the pharmacy profession and establishment of pharmacists, clinical pharmacologist, and others in the pharmacy profession as critically important, indispensable, contributing members of nutrition support teams. The advocacy and clear demonstration of the benefits of a multidisciplinary approach to the provision of consistently safe and effective clinical nutrition to all patients, under all conditions, at all times; and the initiation and organization of nutrition support teams for the establish-
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ment and maintenance of the highest standards of comprehensive and integrated nutritional and metabolic care and treatment, especially of complex, critically ill patients. The subsequent inspiration for, and active stimulation of, the formation and the establishment of multidisciplinary professional, scientific, clinical, educational, and research societies for the advancement of nutritional support, as manifested by such organizations as the American Society for Parenteral and Enteral Nutrition, and almost 100 other similar societies throughout the world. The establishment, beyond a doubt, of the relevance of adequate nutritional support in achieving optimal clinical results, minimizing morbidity and mortality, and improving outcomes in the primary and adjunctive therapy of critically ill patients with a broad range of conditions and under a wide variety of situations. This is especially relevant in the management of patients with significant malnutrition and/or large weight loss secondary to recent anorexia, impaired ingestion, etc. The extent of hospital starvation was documented, and attention was directed appropriately to the vital importance of nutritional support and timing in improving surgical outcomes in malnourished patients. The stimulation of the subsequent intense interest in, and accentuated advancement of, enteral nutrition support as a primary, adjunctive, additional or alternative technique of nutritional support in patients having adequate function of the alimentary tract. This is consistent with the principle that, “if the gastrointestinal tract works normally, or at all, use it.” Myriad advances, techniques, technologies, formulations, and investigations in the area of enteral nutrition were galvanized in response to parenteral nutrition and its success in helping to salvage the most critically compromised, malnourished patients. The demonstration of the desirability and the utility of inducing or allowing a period of “bowel rest” together with TPN support in the management of patients with selected primary conditions or disorders of the gastrointestinal tract, which interfere with digestion, absorption, assimilation of required nutrients, and, are reversible with specific therapy. The management and outcomes of patients with high output gastrointestinal fistulas were significantly improved as a result. The stimulation and augmentation of the studies and analyses of cost/benefit ratio, risk/benefit ratio, morbidity and mortality, and other outcomes, standards, policies, and procedures, regulatory legislation and oversight, national surgical quality improvement programs, credentialing, reimbursement, medical-legal and moral-ethical issues, etc, about nutritional support. The stimulation of the development of specially designed and formulated nutrient solutions for support of
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patients with specific metabolic derangements, such as renal failure, hepatic failure with encephalopathy, pulmonary insufficiency, trauma, immunosuppression, prematurity in infants, and as an adjunct in managing patients who require bone marrow transplantation in their therapy, etc. The stimulation and advancement of the concept of nutrients, either individually, or in various combinations, as “Medical Foods, Nutraceuticals, and Prescription Foods,” for use in the therapeutic and adjunctive specific management of a medical disorder, disease or condition, for example, the use of diets with high arginine content for stimulation of the production of human growth hormone, nitric oxide (NO), etc. The development and advancement of the concept that the practice of clinical nutritional support does not consist merely of the provision of adequate foodstuffs to meet requirements, but can also modulate the biology, biochemistry, biomechanics, immunology, and other manifestations of cellular function to the advantage of the patients’ optimal totalbody physiology, function, performance, productivity, health, longevity, and, ultimately, the quality of life. The development and advancement of the concept, apparatus, technology, expertise, and practical system of ambulatory or home nutritional support, leading to the “virtual explosion” in the outpatient management of patients with complex medical and/or surgical problems, and to the genesis and unprecedented growth of the entire home healthcare industry (currently a multi-billion dollar annual enterprise). The demonstration of the essentiality for fundamental, integrated and continuing comprehensive nutritional education in the curricula of the professional health sciences institutions, in post-graduate specialty training programs, and for life-long learning of all healthcare providers.9 Although currently available knowledge, components, and techniques of parenteral nutritional support have been shown to be utilitarian and life-saving in a wide variety of clinical conditions, TPN support today is still not ideal. Much basic and clinical investigation remains to be accomplished and must be stimulated, undertaken, encouraged, and supported if this technique is to be perfected in order to achieve the ultimate goal of providing optimal nutrition to all patients, under all conditions, at all times.13 In the words of the eminent biochemist and nutritionist, Sir David Cuthbertson,14 “Lest we forget, I would remind you that we all owe our fetal life till parturition to the passage of the nutrients we require from the blood vessels of our mothers into our blood vessels as they traverse the chorionic villi in close relation.” It is important for us to recall that we all began our lives as human beings in utero, receiving our nourishment entirely by vein, and we must continue our quest to attempt to emulate that ideal model of
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intravenous feeding for the support of those who might require a period of TPN for sustaining post-natal life. In summary, longterm TPN was inaugurated successfully as a safe and efficacious basic and clinical feeding technique more than 35 years ago. It has been credited for being instrumental in saving countless lives, and has clearly demonstrated the relevance of adequate nutrition to the achievement of optimal clinical results in surgery patients of all ages, leading to the enormous increase in the use of enteral feeding in all varieties of patients whose oral intakes are inadequate to support normal nutritional status and metabolic function. Furthermore, the subsequently obvious need for special ambulatory and home parenteral and enteral feeding capabilities has stimulated and fueled the unbridled development of home health care in this country. Innovative development and maturation of the technology and techniques that are likely to occur in the future in this hybrid field of clinical biochemistry, biophysics, immunology, molecular biology, genetics, and their inevitable extensions are most promising, almost incomprehensible, and virtually unlimited.13
REFERENCES 1. Moore FD, Brennan MF. Intravenous Feeding. N Engl J Med 1972;287:862–864. 2. Elman R, Weiner DO. Intravenous alimentation with special reference to protein (amino acid) metabolism. JAMA 1939;112: 796–802.
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3. Elman R. Parenteral alimentation in surgery with special reference to proteins and amino acids. New York:Hoeber, Inc;1947. 4. Mann GV, Geyer RP, Watkin DM, et al. Parenteral nutrition. IX. Fat emulsions for intravenous nutrition in man. J Lab Clin Med 1949;34:699–712. 5. Moore FD. Surgical nutrition. Nutr Rev 1948;6:161–164. 6. Moore FD, Olesen KH, McMurrey JD, et al. The body and cell mass and its supporting environment: Body composition in health and disease. Philadelphia:WB Saunders Company;1963. 7. Cahill GF. Control of body fuel utilization during starvation. Conference of Energy Metabolism and Body Fuel Utilization. Edited by AP Morgan Jr. Cambridge: Harvard University Press; 1966;122–135. 8. Geyer RP. Parenteral nutrition. Physiol Rev 1960;40:150–186. 9. Dudrick SJ. A 45-year obsession and passionate pursuit of optimal nutrition support: Puppies, pediatrics, surgery, geriatrics, home TPN, A.S.P.E.N., et cetera. J Parenter Enteral Nutr 2005; 29:272–287. 10. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Longterm total parenteral nutrition with growth, development and positive nitrogen balance. Surgery 1968;64:134–142. 11. Wilmore DW, Dudrick SJ. Growth and Development of an infant receiving all nutrients exclusively by vein. JAMA 1968; 203:140–144. 12. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg 1969;160:974–984. 13. Dudrick SJ. Early developments and clinical applications of total parenteral nutrition. J Parenter Enteral Nutr 2003;27:291– 299. 14. Cuthbertson DP. Historical background to parenteral nutrition. Acta Chir Scand 1980;498(Suppl):20–25.
knowledge of the anatomy and physiology of the circulation; knowledge of the basic biochemical nature of nutrient substrates; knowledge of the interrelationships of these substrates with microbiology, immunology, asepsis and antisepsis; and some knowledge of the complex interactions of food substances with metabolic process, pharmacologic agents, and pathophysiologic conditions. Although various rudimentary, and generally ineffective forms of parenteral nutrition had been attempted clinically sporadically dating back to the early 1900s,1 focused interest and concerted efforts to advance this mode of therapy were heightened and catalyzed in the fourth decade of the last century.2 Robert Elman performed a series of original basic and clinical intravenous feeding experiments and was instrumental in developing intravenous protein hydrolysate substrate solutions that presumably would have led him to the development of a safe and reliable technique of TPN. His investigative work was interrupted abruptly by events related to World War II, in which our Nation’s priorities were shifted dramatically and drastically away from basic scientific medical endeavors to practical wartime efforts. After his return from the war, Elman3 compiled his efforts in a classic tome entitled, “Parenteral Alimentation in Surgery with Special Reference to Proteins and Amino Acids,” and this monograph which was awarded the quinquennial Samuel D Gross Prize of the Philadelphia Academy of Surgery in 1945, was published in 1947. By 1950, the first reports of an effective fat emulsion for intravenous use were published,4 and it became evident that synthetic requirements for protein synthesis and anabolism included the simultaneous administration of adequate caloric substrate to inhibit or minimize the use of administered amino acids for gluconeogenesis, and to provide the energy requirements for peptide bond formation.5 Although most clinicians in the 1950s were aware of the negative impact of malnutrition on morbidity, mortality, and outcomes, apparently only a relatively small percentage of practicing physicians and surgeons understood or expressed the advisability, indeed the necessity, for providing optimal nutritional support for their malnourished patients if optimal clinical results were to be obtained. By 1960, there was demonstration that during caloric starvation, an inevitable loss of nitrogen and a subsequent reduction in total body protein occurred.6 By 1965, it became clear that a complex endocrine interrelationship
Competing Interests Declared: None. Received June 12, 2007; Accepted June 13, 2007. From the Department of Surgery, Yale University School of Medicine, Program in Surgery, Saint Mary’s Hospital/Yale Affiliate, Waterbury, Connecticut. Correspondence address: Stanley J Drudrick, MD, FACS, Saint Mary’s Hospital, Department of Surgery, 56 Franklin St, Waterbury, CT 06706. email: [email protected]
© 2007 by the American College of Surgeons Published by Elsevier Inc.
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governs the use of body fuels, and that this endocrine mediated balance is upset after injury so as to favor endogenous fat mobilization, amino acid release from muscle, and gluconeogenesis.7 But the prevailing dogma during the 1960s was that feeding entirely by vein was impossible; even if it were possible, it would be impractical; even if it were practical, it would be unaffordable. Total parenteral nutrition was considered a “Holy Grail” or “Gordian Knot” pursuit by most physicians and surgeons of that time. This formed a rather intractable wall of ignorance, prejudice, and indifference that had to be penetrated first by developing all of the substrates in forms compatible for delivery to seriously ill patients to provide adequate nourishment intravenously. Second, by demonstrating in the experimental laboratory that such a solution, together with an appropriate, safe, and effective delivery system could provide all essential nutrients in quality and quantity sufficient to support animals for long periods of time. And third, if the animal experiments were successful, applying the techniques and technology to safe, effective, practical use in human beings. I had absolutely no doubt that it would be possible to provide all required nutrient substrates to support cellular metabolism entirely primarily by vein because it is obvious that the vascular circulation is the route by which the body cell mass ultimately receives nutrients. Secondly, my simplified concept of the gastrointestinal tract is essentially that it is a hollow tube that extends from the mouth to the anus and consists of a specialized lining of endothelial cells, together with the attached salivary glands, hepatobiliary system and pancreas, which digest and modify the food substances ingested into the alimentary tract, preparing them suitably for absorption into the portal and lymphatic systems for assimilation into the body cell mass for energy, synthesis, and other physiologic functions. Accordingly, the fundamental problem was to provide all nutrient substances required by the body in forms that could be infused directly into the peripheral blood stream for distribution to all cells and tissues without the necessity of passage initially through the gastrointestinal tract. In the process of attempting to emulate the complex physiology of the gastrointestinal tract in order to bypass its digestive and absorptive functions successfully and effectively by the infusion of all required nutrient substrates intravenously, I gained a great deal of respect for this remarkable multifunctional, multi-organ system. Indeed, I began to tout a cardinal axiom to my students, house officers, colleagues and others that, “The dumbest gastrointestinal tract is smarter than the smartest physician, surgeon, nurse, dietitian, pharmacist, scientist, or nutritionist. This is the inherent fundamental advantage of oral or enteral nutrition over TPN in
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regulating the safety and efficacy of clinical nutritional support.” The most valuable relevant publication available at that time was the monumental summation of the field by Robert P. Geyer,8 entitled “Parenteral Nutrition” and published in Physiological Reviews by the American Physiological Society in January, 1960. It is a 37 page masterpiece citing 659 references; it is the most comprehensive review of published works on parenteral nutrition to that date; and it served as a classic summary and compilation of the most important scientific contributions forming the database upon which ultimately the achievement of TPN was built. Many of the surgical teams that contributed to the early advancement of the original TPN experiences continued, renewed, and intensified their investigative activities in our mutual quest to perfect total intravenous feeding techniques, especially those in Boston, New York, New Haven, and Washington, DC, where many of our contemporary surgical colleagues were actively involved in their training or early academic careers. During the 1970s, in this exciting decade of continuous discovery, modulation of and practical applications for TPN technology and techniques, virtually every Department of Surgery in the country made valuable contributions to the knowledge, experience, and judgment that advanced this important area of endeavor. Several factors account for the persistent and continual stimulation of surgeons and their coworkers to maintain, improve, or optimize the nutritional status of surgery patients under all conditions at all times. The primary impetus for their attention to nutritional status is that surgeons observed throughout the years that operative results, including the rate and quality of wound healing, incidence of complications, and morbidity and survival, were usually best when patients were in good nutritional condition and worst when patients were in poor nutritional condition. A basic etiologic problem is that surgery patients often present with disorders that have impaired their ability to maintain adequate nutrition for some time prior to operation, and/or have impaired or obviated the likelihood, or even the possibility, of obtaining optimal nourishment by conventional alimentary tract routes following operation. Compounding the situation, the primary pathophysiologic condition necessitating the surgical operation, eg, multiple trauma, major burn, extensive neoplasm, often increases the metabolic expenditure of the body’s available calories, protein, and other intermediate substrates for energy and repair, thereby increasing nutrient requirements for homeostasis, recovery, convalescence, and rehabilitation above normal. If the surgery patient is an infant or child, the accentuated nutrient needs for fueling concomitant growth and development introduce a unique pediatric nutritional support problem, further compounding
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the requirements for maintaining metabolic equilibrium throughout the period of surgical diagnosis and treatment. Another nutritional problem indigenous to the practice of surgery is that operative procedures not only inevitably induce or compound existing catabolism, but often temporarily, and sometimes permanently, interfere with the normal digestion, absorption, and assimilation processes at a time when nutritional requirements are usually already increased. The prime example of this situation is massive resection of the small intestine for life-saving indications, resulting in long standing or permanent short bowel syndrome. Finally, the many complicating factors that can occur after major operations, general anesthesia, and major injury secondary to burns or other trauma, such as pneumonia, peritonitis, anastomotic disruption, prolonged ileus, bowel obstruction, enterocutaneous fistula, wound infection or dehiscence, sepsis, shock, and multiple organ failure, can severely aggravate metabolic processes and interfere with restoring normal nutritional status and cellular physiologic function.9 These clinical challenges formed the stimulation and inspiration to develop more effective parenteral means for providing the accentuated nutritional requirements of critically ill patients. Before embarking on this daunting undertaking in the 1960s, we had to identify and assess the prerequisites essential to the development of safe and effective TPN, which included the following:
lutions. This essential requirement for TPN to be successful was contrary to clinical practice standards at the time. It was necessary to concentrate the nutrients required into the volume of water that could be safely metabolized daily in an ill, malnourished patient, and to infuse the mixture at a constant rate over the 24 hours in order to achieve maximum utilization of the accentuated nutrient requirements. ● Maintain asepsis and antisepsis throughout the entire process of solution preparation and delivery. The meticulous and conscientious principles and practices related to sepsis-free TPN solution formulation and infusion, and the compulsive protection and monitoring of the central venous catheter exit site required an extensive re-education program and a major clinical culture change among all healthcare personnel, especially those with the responsibility for attending critically ill surgical patients. ● Anticipate, avoid, and correct metabolic imbalances or derangements. The biochemically and nutritionally active components of TPN solution, coupled with the metabolic consequences and aberrations of a variety of pathophysiologic complications, represented a monumental, unprecedented and unpredictable challenge and undertaking if patient safety was to be preserved during the integration of intravenous nutritional support with treatment of the primary disorder.9
●
Accordingly, the protocol for the development of the essential components of TPN consisted of attempting to achieve the following goals:
Formulate complete parenteral nutrient solutions. Commercially available, medically approved intravenous nutrient substrates did not exist for formulation of nutritionally complete parenteral solutions. So it was not possible to concoct solutions for TPN until all of the components and their mutual compatibility could be determined in our laboratories. ● Concentrate substrate components to hypertonicity (5–6 times isotonicity) without precipitation. This absolutely essential goal was not easily accomplished and required a long, tedious, challenging, and at times, frustrating trial and error process. ● Demonstrate the utility and safety of longterm central venous catheterization. At that time this avenue for percutaneous central venous access was not consistent with standards of care or established safe clinical practices; it was foreign and intimidating to most physicians and surgeons, considered high risk and potentially dangerous, and was not looked on with favor by the medical and surgical hierarchy at that time. Indeed, in many institutions, central venous catheterization was actively resisted or even forbidden. ● Demonstrate efficacy and safety of longterm continuous central venous infusion of hypertonic nutrient so-
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Formulate all required intravenous nutrient substrates Devise sterilization procedures and maintain longterm infusion sterility Design and develop practical percutaneous central venous catheters Develop safe longterm central venous catheterization and continuous infusion techniques, principles, and practices Design safe, durable, reliable, versatile infusion pumps and apparatus Establish metabolic compatibility of TPN components with overall clinical goals and with the pathophysiologic conditions.9
Four decades ago the knowledge, experience, techniques, and technologic constituents of the first longterm TPN system were developed in the basic biochemical and animal laboratories, initially in six intravenously fed Beagle puppies, and, subsequently adapted clinically for the efficacious longterm intravenous support of six critically ill adult surgical patients and a newborn infant before its
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widespread clinical application. The details of the orderly and logical scientific development of the principles and components of the techniques in animals, human infants and adults, together with the related indications, limitations, hindrances, complications, motivational factors, clinical applications, and other special aspects, have been described in some detail and reviewed recently.9-13 The remainder of this manuscript consists of a brief outline and an abridged discussion of some of the legacies of the development and successful clinical application of TPN, as follows: The first demonstration that all nutrients required for normal growth and development in animals (initially in Beagle puppies, and later in other species) could be provided longterm entirely by vein safely and effectively. The first demonstration that all nutrients required for normal growth and development in human beings (initially in a term newborn infant, and later in premature infants and older infants and children) could be provided longterm entirely by vein safely and effectively. The first demonstration that positive nitrogen balance, weight gain, wound healing, reduced morbidity and mortality, improved mental and physical activity, and many other desirable clinical outcomes, could be accomplished longterm in critically ill patients nourished entirely intravenously for as long as indicated or required clinically, or for as long as humanely, economically, morally, and ethically justifiable. The development of a wide variety of compatible, complementary and effective (even potentially synergistic) parenteral macronutrient and micronutrient substrates for standard nutritional support, and for special nutritional and metabolic support of seriously ill patients of all ages with a myriad of conditions with or without complications and collateral factors. Formulation of complete crystalline amino acid solutions, fat and water soluble vitamin mixtures, and trace element solutions (previously non-existent) were developed as essential components of an ostensibly complete intravenous nutrition regimen. The development of safe, effective, practical infusion catheters and insertion devices for percutaneous central venous longterm catheterization and indwelling longevity, together with safe and effective insertion techniques and longterm, sepsis-free, safe and effective maintenance techniques, principles, practices, standards, and technology. Furthermore, the introduction of povidone iodine ointment and occlusive waterproof dressings in the management of the indwelling catheter exit site added greatly to the safety and longevity of longterm central venous catheter placement.
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Development of central venous access and infusion techniques and technology for safe and effective longterm administration of nutritional support solutions, resuscitation fluids and electrolytes, blood products and derivatives, and pharmacotherapy. Percutaneous subclavian and jugular vein catheters, implanted multilumen silicone rubber catheters, reservoir port-catheter devices, PICC lines, and multiple modifications and variations were invented to fulfill perceived needs and to provide viable options for longterm central venous infusion. The stimulation and advancement of the technologic revolution in the development of a variety of infusion pumps for longterm ambulatory administration of nutritional formulations, together with appropriate alarms (infusion complete, air-in-line, fluid infiltration or occlusion, voltage drop, power failure or surge, etc.), other safety features, DC battery back-up for AC power, servomechanisms, miniaturization, portability, precision, dependability, etc. The stimulation of the development and advancement of plastic intravenous fluid bags, reservoirs, infusion tubing, administration apparatus, etc., tailored to specific individual patient requirements, situations, and infusates. Plastic bags and containers originally designed for blood products required modification of the plasticizers and plastics for compatibility with, and longterm tolerance of, the more chemically active TPN components to avoid leaching of plasticizers, plastic microemboli and other toxicity. On the other hand, the use of plastic bags for TPN solutions significantly reduced risks of solution contamination, air embolism, and breakage accidents related to glass containers. The stimulation of technologic advances in pharmacy practices with automated, computerized formulation, preparation and admixture apparatus, filtered laminar air flow work areas, cold sterilization of nutrient components and mixtures by membrane filtration, identification of nutrient:nutrient and nutrient: medication interactions and compatibilities, storage principles (refrigeration, preservation, lyophilization), shelf life of solutions, etc. The advancement of the specialty of clinical pharmacology and stimulation of the development of the specialty of nutrition support among pharmacists; the genesis of specially trained parenteral nutrition solution preparation technicians in the pharmacy profession and establishment of pharmacists, clinical pharmacologist, and others in the pharmacy profession as critically important, indispensable, contributing members of nutrition support teams. The advocacy and clear demonstration of the benefits of a multidisciplinary approach to the provision of consistently safe and effective clinical nutrition to all patients, under all conditions, at all times; and the initiation and organization of nutrition support teams for the establish-
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ment and maintenance of the highest standards of comprehensive and integrated nutritional and metabolic care and treatment, especially of complex, critically ill patients. The subsequent inspiration for, and active stimulation of, the formation and the establishment of multidisciplinary professional, scientific, clinical, educational, and research societies for the advancement of nutritional support, as manifested by such organizations as the American Society for Parenteral and Enteral Nutrition, and almost 100 other similar societies throughout the world. The establishment, beyond a doubt, of the relevance of adequate nutritional support in achieving optimal clinical results, minimizing morbidity and mortality, and improving outcomes in the primary and adjunctive therapy of critically ill patients with a broad range of conditions and under a wide variety of situations. This is especially relevant in the management of patients with significant malnutrition and/or large weight loss secondary to recent anorexia, impaired ingestion, etc. The extent of hospital starvation was documented, and attention was directed appropriately to the vital importance of nutritional support and timing in improving surgical outcomes in malnourished patients. The stimulation of the subsequent intense interest in, and accentuated advancement of, enteral nutrition support as a primary, adjunctive, additional or alternative technique of nutritional support in patients having adequate function of the alimentary tract. This is consistent with the principle that, “if the gastrointestinal tract works normally, or at all, use it.” Myriad advances, techniques, technologies, formulations, and investigations in the area of enteral nutrition were galvanized in response to parenteral nutrition and its success in helping to salvage the most critically compromised, malnourished patients. The demonstration of the desirability and the utility of inducing or allowing a period of “bowel rest” together with TPN support in the management of patients with selected primary conditions or disorders of the gastrointestinal tract, which interfere with digestion, absorption, assimilation of required nutrients, and, are reversible with specific therapy. The management and outcomes of patients with high output gastrointestinal fistulas were significantly improved as a result. The stimulation and augmentation of the studies and analyses of cost/benefit ratio, risk/benefit ratio, morbidity and mortality, and other outcomes, standards, policies, and procedures, regulatory legislation and oversight, national surgical quality improvement programs, credentialing, reimbursement, medical-legal and moral-ethical issues, etc, about nutritional support. The stimulation of the development of specially designed and formulated nutrient solutions for support of
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patients with specific metabolic derangements, such as renal failure, hepatic failure with encephalopathy, pulmonary insufficiency, trauma, immunosuppression, prematurity in infants, and as an adjunct in managing patients who require bone marrow transplantation in their therapy, etc. The stimulation and advancement of the concept of nutrients, either individually, or in various combinations, as “Medical Foods, Nutraceuticals, and Prescription Foods,” for use in the therapeutic and adjunctive specific management of a medical disorder, disease or condition, for example, the use of diets with high arginine content for stimulation of the production of human growth hormone, nitric oxide (NO), etc. The development and advancement of the concept that the practice of clinical nutritional support does not consist merely of the provision of adequate foodstuffs to meet requirements, but can also modulate the biology, biochemistry, biomechanics, immunology, and other manifestations of cellular function to the advantage of the patients’ optimal totalbody physiology, function, performance, productivity, health, longevity, and, ultimately, the quality of life. The development and advancement of the concept, apparatus, technology, expertise, and practical system of ambulatory or home nutritional support, leading to the “virtual explosion” in the outpatient management of patients with complex medical and/or surgical problems, and to the genesis and unprecedented growth of the entire home healthcare industry (currently a multi-billion dollar annual enterprise). The demonstration of the essentiality for fundamental, integrated and continuing comprehensive nutritional education in the curricula of the professional health sciences institutions, in post-graduate specialty training programs, and for life-long learning of all healthcare providers.9 Although currently available knowledge, components, and techniques of parenteral nutritional support have been shown to be utilitarian and life-saving in a wide variety of clinical conditions, TPN support today is still not ideal. Much basic and clinical investigation remains to be accomplished and must be stimulated, undertaken, encouraged, and supported if this technique is to be perfected in order to achieve the ultimate goal of providing optimal nutrition to all patients, under all conditions, at all times.13 In the words of the eminent biochemist and nutritionist, Sir David Cuthbertson,14 “Lest we forget, I would remind you that we all owe our fetal life till parturition to the passage of the nutrients we require from the blood vessels of our mothers into our blood vessels as they traverse the chorionic villi in close relation.” It is important for us to recall that we all began our lives as human beings in utero, receiving our nourishment entirely by vein, and we must continue our quest to attempt to emulate that ideal model of
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intravenous feeding for the support of those who might require a period of TPN for sustaining post-natal life. In summary, longterm TPN was inaugurated successfully as a safe and efficacious basic and clinical feeding technique more than 35 years ago. It has been credited for being instrumental in saving countless lives, and has clearly demonstrated the relevance of adequate nutrition to the achievement of optimal clinical results in surgery patients of all ages, leading to the enormous increase in the use of enteral feeding in all varieties of patients whose oral intakes are inadequate to support normal nutritional status and metabolic function. Furthermore, the subsequently obvious need for special ambulatory and home parenteral and enteral feeding capabilities has stimulated and fueled the unbridled development of home health care in this country. Innovative development and maturation of the technology and techniques that are likely to occur in the future in this hybrid field of clinical biochemistry, biophysics, immunology, molecular biology, genetics, and their inevitable extensions are most promising, almost incomprehensible, and virtually unlimited.13
REFERENCES 1. Moore FD, Brennan MF. Intravenous Feeding. N Engl J Med 1972;287:862–864. 2. Elman R, Weiner DO. Intravenous alimentation with special reference to protein (amino acid) metabolism. JAMA 1939;112: 796–802.
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3. Elman R. Parenteral alimentation in surgery with special reference to proteins and amino acids. New York:Hoeber, Inc;1947. 4. Mann GV, Geyer RP, Watkin DM, et al. Parenteral nutrition. IX. Fat emulsions for intravenous nutrition in man. J Lab Clin Med 1949;34:699–712. 5. Moore FD. Surgical nutrition. Nutr Rev 1948;6:161–164. 6. Moore FD, Olesen KH, McMurrey JD, et al. The body and cell mass and its supporting environment: Body composition in health and disease. Philadelphia:WB Saunders Company;1963. 7. Cahill GF. Control of body fuel utilization during starvation. Conference of Energy Metabolism and Body Fuel Utilization. Edited by AP Morgan Jr. Cambridge: Harvard University Press; 1966;122–135. 8. Geyer RP. Parenteral nutrition. Physiol Rev 1960;40:150–186. 9. Dudrick SJ. A 45-year obsession and passionate pursuit of optimal nutrition support: Puppies, pediatrics, surgery, geriatrics, home TPN, A.S.P.E.N., et cetera. J Parenter Enteral Nutr 2005; 29:272–287. 10. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Longterm total parenteral nutrition with growth, development and positive nitrogen balance. Surgery 1968;64:134–142. 11. Wilmore DW, Dudrick SJ. Growth and Development of an infant receiving all nutrients exclusively by vein. JAMA 1968; 203:140–144. 12. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Can intravenous feeding as the sole means of nutrition support growth in the child and restore weight loss in an adult? An affirmative answer. Ann Surg 1969;160:974–984. 13. Dudrick SJ. Early developments and clinical applications of total parenteral nutrition. J Parenter Enteral Nutr 2003;27:291– 299. 14. Cuthbertson DP. Historical background to parenteral nutrition. Acta Chir Scand 1980;498(Suppl):20–25.