Biomedical subjects
D W Wilmore
Publications and source records attributed to D W Wilmore.
Bowel rehabilitation: an alternative to long-term parenteral nutrition and intestinal transplantation for some patients with short bowel syndrome.
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Management of patients in fast track surgery.
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Can we minimize the effects of opioids on the bowel and still achieve adequate pain control?
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The effect of glutamine supplementation in patients following elective surgery and accidental injury.
The metabolic response to injury, whether a controlled elective surgical procedure or an accidental injury, is characterized by the breakdown of skeletal muscle protein and the translocation of the amino acids to visceral organs and the wound. At these sites, the substrate serves to enhance host defenses, and support vital organ function and wound repair. Glutamine (GLN) plays a major role in these processes, accounting for approximately one third of the translocated nitrogen. From available data, GLN-supplemented intravenous nutrition in patients undergoing elective surgery improves nitrogen balance, helps correct the decreased GLN concentration found in the free intracellular skeletal muscle amino acid pool and enhances net protein synthesis (particularly in skeletal muscle). Six randomized blind trials (two multicentered investigations) reported a decreased length in hospital stay in postoperative patients receiving GLN supplementation. After blunt trauma, GLN supplementation increased plasma concentrations, attenuated the immunosuppression commonly observed and decreased the rate of infection. Patients with burn injury have low GLN plasma and intramuscular concentrations; turnover and synthesis rate are accelerated, yet apparently inadequate to support normal concentrations. These data suggest that GLN supplementation has important effects in catabolic surgical patients, but the exact mechanisms to explain these events remain unknown, and more research is required to explain the apparent benefits of dietary GLN.
Short bowel syndrome.
The short bowel syndrome is a symptom complex that occurs in adults who have less than 200 cm of jejunum-ileum remaining after intestinal resection. Similar symptoms are observed in infants and children following massive bowel resection or congenital anomalies and in individuals with longer segments of intestine with severe mucosal disease. Initial care should focus on a thorough excision of nonviable bowel, an exact measurement of the remaining viable bowel, placing all intestine in continuity at the initial or subsequent operation, and controlling initial food intake. With time, adaptation of the remnant intestine occurs, and absorptive function may be maximized by enhancing the enteral diet and minimizing parenteral nutrition. Growth factors and specialized nutrients may also enhance this process. Intestinal transplantation should be considered in selected individuals with the short bowel syndrome who fail intestinal rehabilitation protocols.
Growth factors in clinical practice.
Growth factors enhance protein synthesis and thus reduce the catabolic response to injury. As a result of bioengineering and new manufacturing techniques several anabolic agents have become available for clinical use and have been evaluated in surgical patients with catabolic illness. Data support the anabolic effects of growth home in such patients, but its expense and possible deleterious effects during the acute phase of illness limit its use to selected patient groups. Insulin-like growth factor-1 has also been studied, but specific indications for its use have not been identified in catabolic patients. Testosterone and derivatives of this hormone exert anabolic effects, but few randomized trials include catabolic surgical patients, and higher doses of some derivative compounds are associated with hepatic dysfunction. Nonetheless, as we move into the future, studies will determine the specific doses for administration of these and other anabolic factors in specific patient groups. Anabolic therapy will shorten the length of therapy and improve the outcome in the future.
Metabolic response to severe surgical illness: overview.
Severe surgical illness results in metabolic responses that mobilize substrate (amino acids and fatty acids) from body stores to support vital organs, enhance resistance to infection, and ensure wound healing. Central to this process is the redistribution of body protein, which moves from skeletal muscle to support the central viscera. If unsupported, this protein-wasting state could result in prolonged convalescence, diminished immunity, and poor wound healing. Present evidence suggests that the central nervous system plays a major role in regulating this protein catabolic response. Infusing exceedingly small quantities of the proinflammatory cytokines into the brain can mimic injury responses, and central cytokine blockade may be one therapeutic approach to attenuating these responses safely in the future. Additional evidence also demonstrates that the function of the hypothalamus and anterior pituitary is dampened during the later stages of severe surgical illness, and the possibility of hormonal replacement therapy needs to be explored.
A weak electrical current enhances intracellular delivery of therapeutic substances.
Cell membranes have electrical properties which can be measured and modified. Administering a weak electrical signal across a tissue is a technique which can be used to determine the quantity of water in the intracellular and extracellular compartments. Using this real-time method of bioelectrical impedance, it was found that a variety of stimuli (including an electrical current) can enhance the passage of water and other substances into the cell. We propose an inexpensive and safe technique which could be utilized to enhance delivery of a wide variety of therapeutic agents into cells for the enhanced delivery of antibiotics, chemotherapy or other therapeutic agents.
Judging surgical research: how should we evaluate performance and measure value?
OBJECTIVE: To establish criteria to evaluate performance in surgical research, and to suggest strategies to optimize research in the future. SUMMARY BACKGROUND DATA: Research is an integral component of the academic mission, focusing on important clinical problems, accounting for surgical advances, and providing training and mentoring for young surgeons. With constraints on healthcare resources, there is increasing pressure to generate clinical revenues at the expense of the time and effort devoted to surgical research. An approach that would assess the value of research would allow prioritization of projects. Further, alignment of high-priority research projects with clinical goals would optimize research gains and maximize the clinical enterprise. METHODS: The authors reviewed performance criteria applied to industrial research and modified these criteria to apply to surgical research. They reviewed several programs that align research objectives with clinical goals. RESULTS: Performance criteria were categorized along several dimensions: internal measures (quality, productivity, innovation, learning, and development), customer satisfaction, market share, and financial indices (cost and profitability). A "report card" was proposed to allow the assessment of research in an individual department or division. CONCLUSIONS: The department's business strategy can no longer be divorced from its research strategy. Alignment between research and clinical goals will maximize the department's objectives but will create the need to modify existing hierarchical structures and reward systems. Such alignment appears to be the best way to ensure the success of surgical research in the future.
Therapy which enhances surgical recovery: the potential for multimodality, fast-track surgery in the 21st century.
Hospital stay will be greatly reduced following major operations in the years to come. Already, minimally invasive procedures, selected anesthetic techniques and the use of appropriate pharmaceutical agents have reduced postoperative hospitalization. However, surgeons and their anesthesiology colleagues have combined many of these therapies in a multimodality approach, which has greatly shortened surgical convalescence following major surgery. The literature reports that patients can be discharged following recovery in 48 hours following a partial colectomy, in 1-2 days following pneumonectomy and in 4-5 days following knee or hip replacement operations. This multimodality approach appears to greatly reduce postoperative stress. Postoperative hospitalization will continue to be reduced throughout the coming century.
Postoperative protein sparing.
Postoperative nitrogen sparing refers to a therapy that decreases net nitrogen loss from the body following an operation. Protein sparing has long been regarded as a surrogate marker for improved outcome, but a critical review of the evidence indicates that this relation is difficult to establish, especially in the short term. Thus, specific endpoints that evaluate outcome are needed to determine the efficacy of a specific therapy that spares protein. Cost effectiveness must also be considered. A variety of therapies were evaluated using protein-sparing, efficiency, and cost criteria. Evidence was reviewed for glucose, amino acids, parenteral nutrition, enteral nutrition, growth hormone, and glutamine administered during the perioperative period. Only three areas could be identified that spared nitrogen and provided efficacy: (1) preoperative total parenteral nutrition (TPN) for 7 to 10 days before operation in a depleted patient (</=15% body weight loss); (2) the use of growth hormone with nutritional support to promote wound healing (especially in burns) and possibly to enhance muscle strength (particularly in the elderly); and (3) the use of glutamine-supplemented TPN in severely ill surgical patients to decrease mortality. The issue of early tube feeding in trauma patients is still confusing. This therapy must be evaluated by an appropriate study in trauma patients that compares a tube-fed group with an unfed control group. Only by demonstrating improved outcomes and enhanced cost saving with our protein-sparing therapy can we continue to enhance the care of our surgical patients.
Overview of intestinal adaptation and its stimulation.
Total parenteral nutrition (TPN) can be life-saving for many patients with short-bowel syndrome (SBS). However, chronic TPN administration is associated with nutritional deficiencies, septic complications, high health care costs, and life-threatening organ failure. In an effort to rehabilitate SBS patients so they may achieve enteral autonomy, investigators have attempted to stimulate the adaptive response following extensive small-bowel resection. Intestinal adaptation may include: 1) morphological changes of the residual bowel which increase the absorptive surface area; 2) functional changes that increase the absorptive capacity of individual enterocytes and colonocytes; and 3) changes in colonic production and absorption of short-chain fatty acids which improve intestinal vitality and maximize efficiency of energy and fluid absorption. Several peptides, nutrients, cytokines, and other factors promote intestinal adaptation in animals. These "growth" factors may predominantly affect one aspect of the adaptive response while having little or no effect on other physiologic or morphologic parameters. In addition, combined administration of stimulatory agents may be necessary to enhance adaptation. Dietary constituents may have profound positive and negative effects on adaptation and must be considered in developing an overall plan for treatment of the SBS patients. Only a few clinical studies have been performed to evaluate therapeutic regimens for SBS beyond standard supportive care and TPN administration. The combined administration of growth hormone, glutamine and a modified diet to over 225 adults has been shown to eliminate or decrease TPN dependence in 80% of patients receiving this therapy. Further study is required to optimize the treatment of humans with intestinal failure and to determine which patients are most likely to benefit from medical therapy. The authors conclude that the intestinal length to body weight index may be one predictive factor useful for determining which SBS patients will benefit from a trial of pharmacologic manipulation before attempting alternative, potentially more invasive therapies.
Deterrents to the successful clinical use of growth factors that enhance protein anabolism.
Participants in competitive sports have demonstrated that the use of growth factors and other anabolic agents enhance human performance, yet physicians are slow to adopt this approach in patients who have a disease-related decrease in strength and activity. Growth factors should be thought of as the next major step forward in providing more efficient and effective nutritional support to catabolic or wasted patients. The obstacles to the use of these agents include: the lack of convincing clinical studies; concerns with safety; anabolic effects and the patient's nutritional status; interaction with diet and route of nutrient administration; the training of health professionals to administer growth factors; and cost. The benefits from these agents should be directly translated into improved patient outcome. To achieve this goal, a uniquely educated group of investigators, working with sophisticated representatives from the pharmaceutical industry, must emerge to construct appropriate protocols and determine desirable endpoints to evaluate the true societal benefits of these agents.
Glutamine in the support of patients following bone marrow transplantation.
Bone marrow transplantation is being utilized with increasing frequency in the treatment of patients with malignancy; it is also being applied to the treatment of patients with genetic diseases and as an adjunct to solid organ transplantation. The high dose cytotoxic chemotherapy, often accompanied by total body irradiation, results in severe catabolism, disruption of the gastrointestinal mucosa and marked immunosuppression. A variety of studies show that the supplementation of the amino acid glutamine, by the enteral or parenteral route, as either the free or dipeptide form, appears safe and efficacious in patients undergoing bone marrow transplantation. Further double-blind controlled clinical trials of glutamine supplementation in patients undergoing bone marrow transplantation and receiving more contemporary treatment, which often includes the administration of novel combinations of cytoreductive agents and hematopoietic growth factors, are warranted.
The use of growth hormone in severely ill patients.
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Skeletal muscle phosphocreatine depletion depresses myocellular energy status during sepsis.
OBJECTIVE: To determine the effects of phosphocreatine (PCr) depletion on myocellular energetics. DESIGN: Randomized controlled study. SETTING: University laboratory. MATERIALS: Thirty-eight adult male Wistar rats (110-121 g). METHODS: The poorly metabolized creatine analogue beta-guanidinopropionic acid, (beta-GPA, 2% of a gel diet) was fed to the rats for 14 days to replace (75%) endogenous PCr stores before cecal ligation and puncture (CLP). Rats were randomized to receive sham operation and gel diet (sham-gel group [n=10]), sham operation and beta-GPA diet (sham-beta-GPA group [n=9]), CLP and gel diet (CLP-gel group [n=10]), and CLP and beta-GPA diet (CLP-beta-GPA group [n=9]). On day 14, all animals underwent operation. Twenty-four hours later, in vivo phosphorus 31-labeled magnetic resonance spectroscopy (31P-MRS) of the gastrocnemius muscle was performed. Muscle samples were collected to determine enzyme activities of beta-hydroxyacyl-CoA dehydrogenase, phosphofructokinase, citrate synthase, and the metabolites adenosine triphosphate (ATP), PCr, inorganic phosphate, and creatine. Free adenosine diphosphate levels, the phosphorylation potential, and free energy change of ATP hydrolysis were then calculated. RESULTS: All animals undergoing CLP but no controls had positive results of blood cultures. Although sham-beta-GPA animals had altered bioenergetics, CLP-beta-GPA rats experienced a greater deterioration of energy state compared with CLP-gel controls. Glycolytic and oxidative enzyme activities were not significantly different between groups and therefore could not explain the observed differences. CONCLUSIONS: There is an overall decrease in energy availability during sepsis, which is worsened by PCr depletion. These changes support the contention that PCr plays an important role as an ATP buffer during systemic infection.
Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study.
Glutamine (Gln) is an important nutrient substrate for lymphocytes and macrophages in vitro. This pilot study evaluated effects of Gln supplementation on circulating lymphocytes and lymphocyte subsets after allogeneic bone marrow transplantation (BMT). Adult patients received either parenteral nutrition supplemented by L-Gln (Gln-PN) or standard Gln-free PN after BMT. Leukocyte and total lymphocyte counts were determined during hospitalization, and flow cytometry studies of peripheral mononuclear cells were performed 1 to 2 weeks after hospital discharge. The Gln-PN group demonstrated a higher percentage of blood lymphocytes during hospitalization. At flow cytometry, patients who received Gln-PN had an increased total lymphocyte count (332 +/- 50 versus 590 +/- 71 cells/microL, P = 0.010); greater numbers of total T lymphocytes (54 +/- 19 versus 229 +/- 70 cells/microL, P = 0.030); and higher CD4+ and CD8+ T-lymphocyte counts in peripheral blood compared with controls. Gln-PN may support lymphocyte recovery after BMT.