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Background: Specific immunonutrients may reduce the incidence of postoperative complications and shorten recovery time. This randomized trial evaluated the clinical efficacy of a fish oil emulsion on outcome and immune function after gastrointestinal cancer surgery., Methods: A total of 206 patients with gastrointestinal or colonic cancer were randomized to receive isocaloric and isonitrogenous intravenous infusions of either soybean oil alone (1.2 g per kg bodyweight per day; control group, 103 analysed) or soybean plus fish oil emulsion (1.0 and 0.2 g per kg per day respectively; treatment group, 100 analysed) over 20-24 h daily for 7 days after surgery., Results: Baseline data were comparable in the two groups. There were fewer infectious complications (four versus 12 on day 8; P = 0.066), systemic inflammatory response syndrome (SIRS) was significantly less common (four versus 13; P = 0.039) and hospital stay was significantly shorter (mean(s.d.) 15(5) versus 17(8) days; P = 0.041) in the treatment group. Total postoperative medical costs were comparable in the two groups (mean(s.d.) US $ 1269(254) and 1302(324) in treatment and control groups respectively; P = 0.424). The median (interquartile range) difference in CD4/CD8 between days 1 and 8 after surgery was + 0.30 (0.06 to 0.79) in patients receiving fish oil and + 0.20 (-0.19 to 0.55) in controls (P = 0.021). No severe adverse events occurred in either group., Conclusion: Fish oil emulsion-supplemented parenteral nutrition significantly reduced SIRS and length of hospital stay. These clinical benefits may be related to normalization of cellular immune functions and modulation of the inflammatory response.

Objectives: To determine the content of glutamine in major food proteins., Subjects/methods: We used a validated 131-food item food frequency questionnaire (FFQ) to identify the foods that contributed the most to protein intake among 70,356 women in the Nurses' Health Study (NHS, 1984). The content of glutamine and other amino acids in foods was calculated based on protein fractions generated from gene sequencing methods (Swiss Institute of Bioinformatics) and compared with data from conventional (USDA) and modified biochemical (Khun) methods. Pearson correlation coefficients were used to compare the participants' dietary intakes of amino acids by sequencing and USDA methods., Results: The glutamine content varied from 0.01 to to 9.49 g/100 g of food and contributed from 1 to to 33% of total protein for all FFQ foods with protein. When comparing the sequencing and Kuhn's methods, the proportion of glutamine in meat was 4.8 vs 4.4%. Among NHS participants, mean glutamine intake was 6.84 (s.d.=2.19) g/day and correlation coefficients for amino acid between intakes assessed by sequencing and USDA methods ranged from 0.94 to 0.99 for absolute intake, -0.08 to 0.90 after adjusting for 100 g of protein, and 0.88 to 0.99 after adjusting for 1000 kcal. The between-person coefficient of variation of energy-adjusted intake of glutamine was 16%., Conclusions: These data suggest that (1) glutamine content can be estimated from gene sequencing methods and (2) there is a reasonably wide variation in energy-adjusted glutamine intake, allowing for exploration of glutamine consumption and disease.

Background: Optimization of postoperative outcome requires the application of evidence-based principles of care carefully integrated into a multimodal rehabilitation program., Objective: To assess, synthesize, and discuss implementation of "fast-track" recovery programs., Data Sources: Medline MBASE (January 1966-May 2007) and the Cochrane library (January 1966-May 2007) were searched using the following keywords: fast-track, enhanced recovery, accelerated rehabilitation, and multimodal and perioperative care. In addition, the synthesis on the many specific interventions and organizational and implementation issues were based on data published within the past 5 years from major anesthesiological and surgical journals, using systematic reviews where appropriate instead of multiple references of original work., Data Synthesis: Based on an increasing amount of multinational, multicenter cohort studies, randomized studies, and meta-analyses, the concept of the "fast-track methodology" has uniformly provided a major enhancement in recovery leading to decreased hospital stay and with an apparent reduction in medical morbidity but unaltered "surgery-specific" morbidity in a variety of procedures. However, despite being based on a combination of evidence-based unimodal principles of care, recent surveys have demonstrated slow adaptation and implementation of the fast-track methodology., Conclusion: Multimodal evidence-based care within the fast-track methodology significantly enhances postoperative recovery and reduces morbidity, and should therefore be more widely adopted. Further improvement is expected by future integration of minimal invasive surgery, pharmacological stress-reduction, and effective multimodal, nonopioid analgesia.

Objective: To determine if growth hormone (GH) and glutamine (Gln) might allow for a reduction in parenteral nutrition (PN) in individuals with short bowel syndrome., Background Data: Following massive intestinal resection, patients frequently sustain severe nutrient malabsorption and are dependent on PN for life. GH treatment with or without Gln might allow for a reduction in PN., Methods: A prospective, double-blind, randomized, placebo-controlled clinical trial performed in 41 adults dependent on PN. Following screening, patients were admitted to an in-house facility for 6 weeks. After 2 weeks of stabilization and dietary optimization, patients were randomized to one of 3 treatment arms (1:2:2 ratio): oral Gln (30 g/day) + GH placebo (control group, n = 9), Gln placebo + GH (0.1 mg/kg per day, n = 16), or Gln + GH (n = 16). Standard criteria based on clinical and laboratory measurements were followed to determine PN volume and content. After 4 weeks of treatment, patients were discharged and monitored; GH and GH placebo were discontinued, but the diet with Gln or Gln placebo was continued for 3 months., Results: Patients receiving GH + Gln placebo + diet showed greater reductions in PN volume (5.9 +/- 3.8 L/wk, mean +/- SD), PN calories (4338 +/- 1858 calories/wk), and PN infusions (3 +/- 2 infusions/wk) than corresponding reductions in the Gln + diet group (3.8 +/- 2.4 L/wk; 2633 +/- 1341 calories/wk; 2 +/- 1 infusions/wk, P < 0.05). Patients who received GH + Gln + diet showed the greatest reductions (7.7 +/- 3.2 L/wk; 5751 +/- 2082 calories/wk; 4 +/- 1 infusions/wk, P < 0.001 versus Gln + diet). At the 3-month follow-up, only patients who had received GH + Gln + diet maintained significant reductions in PN (P < 0.005) compared with the Gln + diet., Conclusions: Treatment with GH + diet or GH + Gln + diet initially permitted significantly more weaning from PN than Gln + diet. Only subjects receiving GH + Gln + diet maintained this effect for at least 3 months.

Background & Aims: We evaluated perioperative plasma endotoxin, plasma soluble CD14 molecule (sCD14), plasma endotoxin inactivation capacity (EIC) changes and clinical outcome after glutamine was provided in parenteral feedings to patients on whom gastrointestinal operations were performed using a prospective, randomized, double-blind study design., Methods: Forty patients undergoing gastrointestinal operations were randomized into two groups, each had 20 patients. One group received standard parenteral nutrition and the other received the same formulation but supplemented with the dipeptide alanyl-glutamine, the two groups were isonitrogenous. The infusion was started from 1 day before operation to the 3rd day after operation for 5 days. Blood samples were collected on the morning of 1 day before operation, 3h after operation, and on the morning of 1, 4 and 7 days after operation and analyzed for plasma endotoxin level, plasma sCD14 level and EIC., Results: There were no differences between the two groups on plasma endotoxin level. After surgery a rapid reduction in plasma EIC was observed in both groups, a significant restoration of the plasma EIC was observed on the morning of 1 and 4 days after surgery in the study group (0.12+/-0.02 and 0.078+/-0.022 EU/mL, respectively, P < 0.01). A significant rise in plasma sCD14 level was found in the study group on the morning of 1 and 4 days after surgery (14.32+/-1.69 and 10.34+/-1.14 microg/mL, respectively, P < 0.01). Shortened hospital stay was observed in the study group (11.7+/-2.0 days in the control group and 10.6+/-1.2 days on the study group respectively, P = 0.03)., Conclusion: Perioperative parenteral nutrition supplemented with dipeptide alanyl-glutamine ameliorated postoperative immunodepression without direct effect on endotoxemia.

The number of Ph.D. faculty in clinical departments now exceeds the number of Ph.D. faculty in basic science departments. Given the escalating pressures on academic surgeons to produce in the clinical arena, the recruitment and retention of high-quality Ph.D.s will become critical to the success of an academic surgical department. This success will be as dependent on the surgical faculty understanding the importance of the partnership as the success of the Ph.D. investigator. Tighter alignment among the various clinical and research programs and between surgeons and basic scientists will facilitate the generation of new knowledge that can be translated into useful products and services (thus improving care). To capitalize on what Ph.D.s bring to the table, surgery departments may need to establish a more formal research infrastructure that encourages the ongoing exchange of ideas and resources. Physically removing barriers between the research groups, encouraging the open exchange of techniques and observations and sharing core laboratories is characteristic of successful research teams. These strategies can meaningfully contribute to developing successful training program grants, program projects and bringing greater research recognition to the department of surgery.

Diarrhoea, malabsorption and malnutrition characterize the short-bowel syndrome. Following the initial intestinal resection, complications such as fistulas and intra-abdominal abscesses may occur, but these usually resolve with appropriate surgical care. All residual intestine should be placed in continuity before serious attempts at rehabilitation with oral feedings are initiated. Small hourly oral feedings composed of food items high in complex carbohydrate and low in fat are started when appropriate and the diet is gradually increased as intestinal adaptation occurs. The goal during this process is to prevent diarrhoea and allow the formation of semiformed stools. With time, parenteral nutrition (PN) can be reduced, and the time required depends on both length of residual bowel and the particular anatomy involved-for example, the presence or absence of the colon. A programme of optimal diet plus growth hormone (0.1 mg/kg) and oral glutamine (30 g/day) enhances the adaptive process and allows many patients independence from PN. However, those with extremely short segments of jejuno-ileum (<50 cm) and no colon have excessive fluid and electrolyte losses, and intestinal transplantation may be the only therapy which allows such patients to be independent of PN.

The objective of this study was to evaluate the effects of recombinant human growth hormone (GH) on cell immune function, intestinal barrier function, and outcome. A placebo-controlled randomized double-blind trial was performed, with 20 patients undergoing abdominal surgery enrolled in the study. The patients in the study group received GH (0.3 IU/kg/day) subcutaneously from day 3 before operation until day 7 after operation. The patients in the control group received placebo injections. All the patients were given isonitrogenic (0.15 g N/kg/day) and isocaloric (20 kcal/kg/day) parenteral nutrition from preoperative day 1 through postoperative day (POD) 6. The serum GH and insulin-like growth factor-1 (IGF-1) levels, intestinal permeability, peripheral CD4+/CD8+ lymphocyte subsets, and routine blood and biochemistry analyses were evaluated before and after GH treatment. In the study group a significant increase in serum levels of GH and IGF-1 was observed on PODs 3 and 7. A significant decrease in the CD4+ subset population and the CD4+/CD8+ ratio was observed in the control group on POD 7 compared with preoperative studies, whereas no change was observed in the study group. The lactulose/mannitol excretion (L/M) ratio in the control group was elevated significantly on POD 7 compared with that before operation ( p = 0.01), whereas the L/M ratio in the study group did not change compared to preoperative values ( p = 0.08). No adverse reactions were related to the administration. There were no differences observed in operation-related complications or postoperative hospital stays between the two groups. This small pilot study suggests that GH attenuated the depression in cellular immunity following surgical stress and possibly reduced the increase in intestinal permeability that occurs following operation. Further studies of a large group of patients are needed to determine if these changes can be translated into improved outcome in surgical patients.

Objective: To evaluate the evolution of knowledge concerning the stress response in surgical patients and to determine the therapeutic benefit of stress reduction therapy., Summary Background Data: The stress response in surgical patients is associated with tissue catabolism, organ failure, and prolonged recovery. Understanding the neural-hormonal basis for these events has stimulated efforts to attenuate these undesirable effects. A review of the results of these efforts is important for the application of stress reduction therapy and further improvement of surgical care., Methods: Medline was searched from 1980 to the present using the terms "stress response," "neural-hormonal response," "fast track surgery," and "outcome in surgical patients." These papers were reviewed along with historical information relating to early descriptions of metabolic and stress responses in surgical patients., Results: Improved understanding of the stress response in surgical patients has occurred over the past 70 years. Multiple examples of stress reduction associated with decreased morbidity and mortality are reported., Conclusions: Reduction of stress in surgical patients has improved outcome. The use of stress reduction techniques will continue to expand and contribute to the improvement of future surgical care.

Objective: To evaluate the effect of modifying perioperative care in noncardiac surgical patients on morbidity, mortality, and other outcome measures., Background: New approaches in pain control, introduction of techniques that reduce the perioperative stress response, and the more frequent use of minimal invasive surgical access have been introduced over the past decade. The impact of these interventions, either alone or in combination, on perioperative outcome was evaluated., Methods: We searched Medline for the period of 1980 to the present using the key terms fast track surgery, accelerated care programs, postoperative complications and preoperative patient preparation; and we examined and discussed the articles that were identified to include in this review. This information was supplemented with our own research on the mediators of the stress response in surgical patients, the use of epidural anesthesia in elective operations, and pilot studies of fast track surgical procedures using the multimodality approach., Results: The introduction of newer approaches to perioperative care has reduced both morbidity and mortality in surgical patients. In the future, most elective operations will become day surgical procedures or require only 1 to 2 days of postoperative hospitalization. Reorganization of the perioperative team (anesthesiologists, surgeons, nurses, and physical therapists) will be essential to achieve successful fast track surgical programs., Conclusions: Understanding perioperative pathophysiology and implementation of care regimes to reduce the stress of an operation, will continue to accelerate rehabilitation associated with decreased hospitalization and increased satisfaction and safety after discharge. Developments and improvements of multimodal interventions within the context of "fast track" surgery programs represents the major challenge for the medical professionals working to achieve a "pain and risk free" perioperative course.

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.

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.

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.

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., (Copyright 2000 Harcourt Publishers Ltd.)

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.

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.

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.

New approaches to nutritional support are necessary to test therapies that may potentially enhance outcomes. Such approaches include the move to rely on the enteral route for nutrient delivery, the ability to reduce exogenous calories in our nutritional support systems, the need to utilize nutrients for their pharmacological effects, the ability to use growth factors to enhance nutrient efficacy, and the ability to institute nutritional supplementation before elective operations, thus practicing preventative nutrition. Testing these approaches in the years to come should allow us to identify modalities that will permit us to move away from nutritional therapy as a supportive modality and use it as a primary or secondary method of patient care.

Loss of body cell mass, the active functioning tissue of the body, commonly occurs in patients with human immunodeficiency virus (HIV) infection, and the extent of wasting is related to the length of survival. We evaluated the anabolic role of the amino acid L-glutamine (GLN) and antioxidants in a double-blind, placebo-controlled trial in 26 patients with > 5% weight loss since disease onset. Subjects received GLN-antioxidants (40 g/d) in divided doses or glycine (40 g/d) as the placebo for 12 wk. Throughout the study, the subjects were seen weekly by a nutritionist, and body weight, bioelectric impedance assessment, and nutritional counseling were performed. Twenty-one subjects completed the study, and the groups were well matched. The 5 patients excluded from analysis all met a priori exclusion criteria. Over 3 mo, the GLN-antioxidant group gained 2.2 kg in body weight (3.2%), whereas the control group gained 0.3 kg (0.4%, P = 0.04 for difference between groups). The GLN-antioxidant group gained 1.8 kg in body cell mass, whereas the control group gained 0.4 kg (P = 0.007). Intracellular water increased in the GLN-antioxidant group but not in the control group. In conclusion, GLN-antioxidant nutrient supplementation can increase body weight, body cell mass, and intracellular water when compared with placebo supplementation. GLN-antioxidant supplementation provides a highly cost-effective therapy for the rehabilitation of HIV+ patients with weight loss.

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.

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.

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 (

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.

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.