美国胃肠外和经肠营养学会第25届周年纪念临床会议

 

美国胃肠外和经肠营养学会第25届周年纪念临床会议

美国伊利诺州芝加哥

2001年1月21-24日

Conference Report
American Society for Parenteral and Enteral Nutrition
25th Anniversary Clinical Congress
Chicago, Illinois
January 21-24, 2001

Todd Canada, PharmD, BCNSP

 

Introduction

The American Society for Parenteral & Enteral Nutrition (ASPEN) recently celebrated its 25th Anniversary Clinical Congress in Chicago, the city where it all began. The topics have certainly changed over the last 25 years; however, the multidisciplinary nature of the organization has remained consistent and has contributed to the latest developments in nutritional and metabolic research. This report focuses on new developments in adult parenteral multivitamin formulations, the emerging field of prebiotics and probiotics in promoting health and preventing disease, and the innovative nutritional and pharmacologic approaches to cancer-related cachexia.

Pending Changes in Adult Parenteral Multivitamin Formulations

The importance of parenteral multivitamins for patients who are unable to adequately absorb oral multivitamins has been emphasized within the last 15 years by the multiple national shortages of parenteral adult and pediatric multivitamins. Several cases of refractory lactic acidosis due to thiamine deficiency occurred in home parenteral nutrition patients and resulted in significant morbidity and mortality.^[1-3] Now that the shortage of both forms of parenteral multivitamins has been resolved, the US Food and Drug Administration (FDA) has notified manufacturers of the adult products to reformulate to new FDA specifications.^[4]

Why Did it Take so Long to Change?

Notably, the new specifications (Table) are not from recently derived data, but rather from a public workshop that was held in August 1985 and sponsored by the FDA's Division of Metabolic and Endocrine Drug Products and the American Medical Association (AMA)'s Division of Personal and Public Health Policy. Evidently, the clinical testing of the 1975 AMA multivitamin formulation prompted the new recommendations to increase the dosage of vitamins B₁, B₆, C, and folic acid and to add vitamin K to the available adult products. The pediatric multivitamin formulation currently available has 200 mcg vitamin K₁ (phylloquinone) per vial. It is unclear why it has taken 15 years for these recommendations to be implemented. Astra-Zeneca and Baxter have responded to the new FDA changes and do not expect to have updated products on the market for another 18 months unofficially.

Clinical Considerations With the New Multivitamin Formulations

Many healthcare practitioners have expressed concerns over the addition of vitamin K₁ to the new adult multivitamin formulation. These concerns are related to the long-term complications associated with vascular access in the home parenteral nutrition patient population. The use of oral anticoagulants, such as warfarin, to maintain catheter patency is often required in these patients. Since low doses (0.5-2.0 mg) of vitamin K₁ can fully reverse the anticoagulant effects of warfarin, the dosage increase (from 0 to 0.15 mg) in the new multivitamin formulation has many worried that loss of adequate anticoagulation may result in patient morbidity and further malnutrition, possibly after loss of venous access. It is often difficult to provide oral anticoagulation to patients with significant gastrointestinal resections or malabsorptive syndromes, including short bowel syndrome, because of their erratic absorption of warfarin. The concerns may become even more realistic when the amount of vitamin K₁ contributed from fat emulsions is included in the total daily vitamin K₁ dose (eg, approximately 300 mcg of vitamin K₁ is in Intralipid 20% 500 mL).

Patients receiving home parenteral nutrition will likely be pleased with the addition of vitamin K to the multivitamins, as they will no longer be required to add it to their solutions daily or weekly due to the photodegradation of vitamin K in the presence of sunlight. It will also be beneficial since the vitamin K-dependent protein, osteocalcin, is one of the most abundant noncollagenous proteins in bone. This may impede or retard the development of metabolic bone disease in the population receiving long-term home parenteral nutrition.

The higher dose of vitamin C may have implications in the development of hyperoxaluria and its contribution to nephrolithiasis. Since oxalate is a metabolite of vitamin C, patients with renal insufficiency or renal disease and a prior history of nephrolithiasis may be at risk. Another population at risk includes patients with short bowel syndrome with an intact colon presenting with hyperoxaluria and calcium oxalate kidney stones. If an oxalate-restricted diet does not reduce the hyperoxaluria, oral calcium supplements may help bind the oxalate in the foods consumed and facilitate losses in the stool of these patients. Unfortunately, the oxalate from vitamin C degradation can also bind with calcium salts if present in the parenteral nutrition solution, which may be another reason to add the parenteral multivitamin just prior to infusion to minimize contact time, especially in the home setting.

Nutritional deficiencies in the vitamin cofactors (folate, B₆, and B₁₂) have been observed in patients with elevated homocysteine concentrations.^[5] These cofactors are required for homocysteine metabolism and after supplementation have been reported to normalize the plasma homocysteine concentration within 2-6 weeks. In patients receiving parenteral multivitamins, it is hoped that the increases in vitamin B₆ and folic acid will prevent hyperhomocysteinemia, given its association with thrombosis and vascular disease. This would parallel the trend of reduced mortality from cardiovascular causes since the 1960s that has accompanied the increase in vitamin B₆ supplementation in the food supply. The increases in vitamin B₆ and folic acid may also have implications in reducing the risk of catheter-associated thrombosis from hyperhomocysteinemia, since the minimum effective dose of these cofactors is yet to be determined.

Parenteral Nutrition Stability and Compatibility Concerns

The use of a new adult multivitamin formulation may present stability and compatibility issues. However, the higher dose of vitamin C may be beneficial given its instability in the presence of oxygen (degraded to oxalate). Vitamin stability in parenteral nutrition solutions is influenced by several factors, including pH, temperature, preservatives (bisulfite), storage time, and light exposure. The primary compatibility issue would involve the interaction between calcium salts and the vitamin C degradation product, oxalate, as discussed earlier.

Prebiotics and Probiotics in Health and Disease

The role of diet in nutrition and health continues to change as the science of nutrition evolves. Although most us view foods as basic essential building blocks for growth and maintenance of body tissues, the ideal focus is on understanding how our diet may affect or modulate our risk for disease through its effect on physiologic or functional processes occurring within the body. Promising research has specifically evaluated the physiologic functions of intestinal bacteria to maintain and support health. This has led to the development of functional foods being directed at beneficially affecting the gastrointestinal tract to maintain overall health.

Bacteria Within the Gastrointestinal Tract

Human beings are a complex ecosystem containing bacteria that live in a symbiotic relationship. The normal intestinal flora of the human colon contains approximately 10¹¹ bacteria per gram of feces. Anaerobic bacteria, such as Bacteroides, Eubacterium, Lactobacillus, and Bifidobacterium, manifesting as hundreds of individual strains, comprise approximately 99% of the normal intestinal flora. These organisms provide a stable microenvironment that prevents pathogens, such as Clostridium difficile, from colonizing and multiplying in the gastrointestinal tract. The importance of our intestinal flora is best evaluated over the life cycle because of different species of bacteria occurring in human feces at various ages. At birth, we are born with a relatively sterile gastrointestinal tract that becomes dependent on numerous factors throughout life, including maternal flora, the route of delivery (vaginal vs cesarean section), early environmental exposure (home vs hospital), microbial exposure, diet, antibiotics, and the host itself to affect its overall endogenous bacterial flora. Because of these factors, we are all left with very distinct intestinal flora.

New research has emphasized the role of food and the intestinal flora in maintaining mucosal integrity. This specifically involves the use of prebiotics, which are primarily of vegetable origin, to promote the growth of beneficial gut bacteria such as bifidobacteria. Additionally, the concept that ingested bacteria (Lactobacillus) could have a positive influence on the normal microbial flora of the intestinal tract was introduced almost 100 years ago as yogurt.^[6] This gave way to the concept of probiotics, which, when ingested, could prevent or treat an intestinal disease.

What Has Happened to Our Bacterial Food Supply?

Over the last century, the number of pathogens in our food supply has steadily decreased due to processes such as pasteurization. The concept that reducing the pathogenic bacteria in food reduces disease is easily understood; however, reducing the nonpathogenic bacteria in food may have other implications in health and disease that are not fully understood. This is where prebiotics and probiotics may have a role in health and disease prevention. The primary area of focus for prebiotics and probiotics is gastrointestinal infections, which represent a major clinical health problem worldwide. The identification of microbial resistance to antibiotics currently available today and the increasing demand on the pharmaceutical industry to develop effective new antibiotics have led to renewed interest in the possibility of feeding beneficial microorganisms to humans as an alternative to antibiotic therapy for gastrointestinal disorders. Additionally, probiotics offer an attractive treatment alternative secondary to the effects that antibiotics have on delaying recolonization of the normal intestinal flora. There have also been numerous in vivo and in vitro studies to show that the normal intestinal flora provide an effective barrier against pathogenic and opportunistic microorganisms.^[7]

What Are Prebiotics?

The generally accepted definition of a prebiotic is a nondigestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or the activity of one or a limited number of bacteria in the colon and thus improves the host's health.^[8] The available agents are the inulin-type fructans, which include native inulin, enzymatically hydrolyzed inulin or oligofructose, and synthetic fructooligosaccharides. The average daily consumption of inulin and oligofructose is estimated at 1-4 grams in the United States, and these prebiotics are present in a significant number of miscellaneous fruits and vegetables. The most common sources are wheat, onions, banana, garlic, and leeks.^[9]

Prebiotics must resist digestion (hydrolyzation) in the upper part of the gastrointestinal tract and are evidently not absorbed to any significant extent. They are then selectively fermented by endogenous anaerobic microorganisms in the colon to short-chain carboxylic acids (acetate, propionate, and butyrate) and lactic acid, thereby directly providing metabolic substrates to the colonocytes. This fermentation leads to the selective stimulation of growth of the bifidobacteria population. The production of lactic acid acidifies the colonic contents and raises the concentration of ionized minerals, specifically calcium and magnesium. This promotes conditions within the colon for passive diffusion of these minerals. Human studies have corroborated the beneficial effects of inulin and oligofructose on the absorption and balance of dietary calcium.^[9]

Role of Prebiotics. The reported clinical effects of prebiotics include a definite improvement in constipation, improved absorption of calcium (as mentioned above), questionable improvement in total serum cholesterol and low-density lipoprotein cholesterol, and reduction in colon carcinogenesis (animal studies only). The advantages of these agents include their widespread availability, lack of potential infectious risk, and low cost. Prebiotics are generally accepted as safe for use; however, 1% to 4% of the population may have a higher sensitivity for adverse reactions, including anaphylaxis.

Future considerations for prebiotic use have been in the setting of inflammatory bowel disease, short bowel syndrome, necrotizing enterocolitis, and post-bowel transplantation due to their effects on proliferating the growth of bifidobacteria and providing short-chain carboxylic (fatty) acids.

What Are Probiotics?

A probiotic refers to a live, human-derived microorganism that, when ingested, survives passage through the gastrointestinal tract and results in beneficial effects on the host, including amelioration or prevention of a specific disease state.^[10] These agents have been used in veterinary medicine for years with beneficial effects, namely in newborn chickens treated with Lactobacillus to reduce Salmonella growth in their feces (and to reduce the health risks associated with Salmonella infections in humans consuming egg products).

The most common probiotic agents used are Lactobacillus species and bifidobacteria (both are lactic acid bacteria). These two genera of bacteria resist gastric acid, bile salts, and pancreatic enzymes; they adhere to the intestinal mucosa and readily colonize the intestinal tract transiently.^[11] Lactobacillus species are the organisms used to ferment milk products, such as yogurt. They also beneficially secrete lactase to aid in carbohydrate digestion. Lactase hydrolyzes lactose to galactose and glucose, thereby reducing diarrhea and flatulence in lactose-deficient individuals.

The benefits of probiotics may result from the following postulated mechanisms of action:

• acidification of the gut lumen

• in vitro production of antimicrobial substances

• inhibition of pathogenic bacterial adhesion to the mucosal intestinal surface

• decreased bacterial translocation and altered mucosal barrier

• altered cytokine production or immunomodulation (increased serum IgA)

• modification of gut toxins (bacterial antigens) or competition for toxin receptors

• competition for nutrients

• modification of other gut functions

Clinical Uses of Probiotics. Probiotics have been used predominantly in the prevention or treatment of diarrheal disease, with fewer studies in the areas of cancer prevention or the formation of carcinogens, hypocholesterolemic effects, and stimulation of the immune response.^[12] They have been shown to reduce the duration and severity of viral diarrhea, specifically rotavirus in infants. They have also been shown to reduce the risk or incidence of the following:

• traveler's diarrhea

• relapsing Clostridium difficile diarrhea

• antibiotic-associated diarrhea

• diarrhea in daycare centers

Unfortunately, the majority of studies have been poorly designed secondary to inadequately defined strains of microorganisms, variation in the preparation and storage of the probiotics, small sample size, and imprecise definitions of end points, making these trials nonreproducible from other investigators. However, a recent trial of chronic pouchitis, a long-term complication after ileal reservoir surgery for ulcerative colitis, is worth examining.

Pouchitis is the nonspecific inflammation of the ileal reservoir after pouch surgery for ulcerative colitis. After 10 years, its cumulative frequency is approximately 50%. It is characterized by increased stool frequency, urgency, abdominal cramping, and discomfort. Pouchitis is thought to represent an unavoidable response to fecal stasis and an unstable microflora with reduced counts of lactobacilli and bifidobacteria. Gionchetti and colleagues^[13] compared the effects of an oral probiotic preparation (VSL#3) with very high bacterial concentrations of 8 different bacterial strains (4 strains of Lactobacillus, 3 strains of Bifidobacterium, and 1 strain of Streptococcus salivarius subspecies thermophilus) to placebo for 9 months in 40 patients with chronic relapsing pouchitis. The mean patient age was 33 years. Similar durations and relapses of disease were seen in the two groups. Of the placebo group, all 20 (100%) patients had relapses within 4 months vs 3 (15%) VSL#3 patients with relapses within 8 months (P < .001). Interestingly, after the completion of the 9-month study treatment, all of the VSL#3 patients relapsed within 4 months. The fecal concentrations of lactobacilli, bifidobacteria, and Streptococcus salivarius subspecies thermophilus returned to baseline concentrations within 1 month of stopping the probiotic. This emphasizes how the effects of probiotics are not sustained long term after they are discontinued, and chronic treatment is required for continued health benefits. Additionally, no major adverse effects were reported in this 9-month trial.

Safety Concerns of Probiotics. There are potential safety concerns with probiotics since they are live microorganisms with a potential for disease and antibiotic resistance. Rare case reports have been published of patients who have developed Lactobacillus or Saccharomyces (a yeast preparation) bacteremia/sepsis following use of these agents. The fundamental theory that any bacteria or fungus may translocate from the intestinal mucosa confirms that probiotic agents also carry this risk.

Future Study of Probiotics. The potential uses for probiotics include control of inflammatory diseases (such as Crohn's disease or ulcerative colitis), treatment and prevention of allergy, cancer prevention, immune enhancement/stimulation, and treatment of bacterial vaginitis. When more precise information on the mechanisms by which probiotics exert their beneficial effects in vivo is known, this will provide the scientific rationale for the selection of the most appropriate probiotic strains to perform large, double-blind, controlled trials in various gastrointestinal-related diseases. Until then, consider that many of the probiotic preparations available do not have adequate amounts of bacteria in them to sustain colonization of the intestinal tract in their normal doses, and various species of probiotics have very different effects that need proper evaluation in each disorder studied.

What Are Synbiotics?

These are combinations of prebiotics and probiotics that beneficially affect the host by improving the survival and the implantation of live microbial dietary supplements in the gastrointestinal tract. They selectively stimulate the growth and/or activate the metabolism of one or a limited number of health-promoting bacteria.^[9] The use of synbiotics will require further research to determine the most appropriate combinations of agents and doses of each, as well as the vehicles (powder, solution, capsule, etc) used to administer them, along with the associated oral diet to complement it. Ideally, a synbiotic would provide purposeful modification of the microbial flora to benefit overall host health.

Nutritional and Pharmacologic Approaches to Cancer-Related Cachexia

Malnutrition in Cancer

One of the important factors in the response to treatment and mortality is the overall condition of the host at the time of cancer diagnosis. Approximately 50% of cancer patients will have experienced weight loss at the time of diagnosis, and this imparts a poor prognostic sign. This often results in loss of independence and reduces the quality and duration of life. By the time of death, nearly all cancer patients will have experienced some degree of weight loss. Cancer has one of the highest incidences of protein-calorie malnutrition among hospitalized patients. The protein-calorie malnutrition is often related to the disease itself, treatments associated with the disease, or both. Patients with an apparently identical primary cancer and disease stage may vary significantly in terms of the development of cachexia, characterized as the loss of body cell mass or lean body mass, anorexia, malnutrition, and ultimately debilitation. The development of cachexia may be related to variations in tumor phenotype and host response, although the precise etiology is unknown.

Effects of Weight Loss in Cancer Treatment

The effects of weight loss in cancer were originally described by the Eastern Cooperative Oncology Group,^[14] who evaluated the prognostic effect of weight loss on response to chemotherapy and survival in 3047 patients and assessed the frequency of weight loss in a variety of tumor types. Chemotherapy response rates were lower overall in the patients with weight loss; however, only in patients with breast cancer was this statistically significant (response rate of 61% without weight loss vs 44% with weight loss, P =.01). Within each tumor type evaluated, survival was shorter in the patients who had experienced weight loss than in those who had not. They noted that 46% of patients had no weight loss in the previous 6 months; this subpopulation comprised mainly patients with non-Hodgkin's lymphoma, breast cancer, acute nonlymphocytic leukemia, and sarcoma tumor types. The remaining 54% of patients had lost weight of varying degree: between 0% and 5% of their body weight, 5% to 10% of their body weight, or greater than 10% of their body weight. Of the patients reporting greater than 10% weight loss, most had pancreatic or gastric cancers. These study findings emphasized the importance of preexisting malnutrition in patients about to undergo chemotherapy.

Etiologies of Weight Loss in Cancer

The primary determinants of weight loss in cancer represent a multifactorial process. The most common reasons for weight loss are generally decreased oral intake of nutrients, increased requirements either from the tumor or associated treatments, and inefficient use of nutrients.^[15] Tumors of the gastrointestinal tract may present a physical obstruction or induce a malabsorptive state, thereby reducing oral intake or its absorption. There are several reasons for decreased oral intake, namely the gastrointestinal symptoms (nausea, vomiting, dysgeusia, early satiety, and xerostomia) associated with weight loss seen in cancer.

During simple starvation, the normal host is able to adapt by reducing energy expenditure, conserving protein, and using fatty acids and ketone bodies derived from fat as an energy source. These adaptations are attenuated or absent in cancer cachexia, where energy expenditure may be increased and ongoing protein losses continue. Increased requirements may be a direct effect of increased energy expenditure. Resting energy expenditure (REE) in cancer patients represents a heterogeneous description from hypometabolism to hypermetabolism. In an evaluation of 200 cancer patients, the mean measured REE was 98.6% of predicted value using the anthropometric-based formula of Harris and Benedict (~ 22-25 kcal/kg/day).^[16] However, it was noted that 33% were hypometabolic (measured REE < 90% of predicted), 41% were normometabolic (measured REE 90% to 110% of predicted), and 26% were hypermetabolic (measured REE > 110% of predicted). Patients who were characterized as hypermetabolic had a longer duration of disease than the normometabolic patients (32.8 vs 12.8 months), indicating that duration of malignancy may have some impact on energy metabolism.

Several changes in nutrient metabolism have been described in patients with cancer cachexia. These patients exhibit a degree of glucose intolerance and insulin resistance with increased rates of glucose production and recycling via lactate (from the Cori cycle). Lipolysis rates have not been found to be significantly increased, and lipogenesis appears to be reduced.^[15] Whole body protein turnover has been observed to be increased in most advanced cancer patients compared with starved normal individuals and weight-losing noncancer patients. As expected with progression of disease, protein turnover appears to increase further. Cancer patients with advanced disease and weight loss appear to exhibit an impaired adaptability to simple starvation, since fat mobilization is impaired and muscle proteolysis persists. All of these alterations in metabolism have been referred to as inefficient use of nutrients. Additionally, if surgery is required as part of the cancer treatment, it may also cause alterations in nutrient metabolism with an increased energy expenditure and protein requirement. It becomes obvious that replenishing the metabolic deficiencies of the cancer patient is clearly not a simple process.

Role of Cytokines in Cachexia

Cachexia is viewed as a multidimensional adaptation encompassing a variety of physiologic alterations that include increased core body temperature and resting energy expenditure, stress hormone response (cortisol, epinephrine), skeletal muscle wasting, increased hepatic acute-phase response, trace mineral sequestration (copper), decreased intestinal motility, bone marrow suppression, and diuresis.^[17] It involves a coordinated acute-phase response, which involves the hepatic synthesis of large quantities of proteins. There is also an energy-intensive component to this acute-phase response along with the requirement for large quantities of essential amino acids to synthesize the hepatic proteins.

The acute-phase response is regulated by the production of cytokines, with most of the clinical research focusing on tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, although it is understood that other cytokines decide this as well. The predominant cytokine effect is locally mediated and is paracrine and autocrine in nature. Anorexia results from the central effect of cytokines on the hypothalamus to alter feeding behavior. The peripheral insulin resistance observed with altered carbohydrate metabolism is also mediated by proinflammatory cytokines.

Studies to date have been unable to correlate serum levels of cytokines to the degree of malnutrition observed in cancer patients.^[18] The primary reason for this is the site-specific and concentration-dependent nature of cytokine-mediated reactions. It is the cellular or tissue response to cytokines, not the changes observed in the serum or plasma cytokine concentrations.

Pharmacologic Modulation of Cachexia With Anticytokine Therapies

One of the most rational pharmacologic treatments for cachexia is to use an agent that inhibits protein breakdown, since protein synthesis rates are likely already elevated to compensate for the hypercatabolic state. Inhibition of proinflammatory cytokine activity can decrease protein breakdown and is observed with megestrol acetate, medroxyprogesterone, and tetrahydrocannabinol in vitro.^[17] Thalidomide and melatonin also have anti-TNF activity and are promising agents in achieving weight gain when other conventional treatments have failed. Additionally, anti-inflammatory therapies offer yet another direction to modulate proinflammatory cytokine activity due to their effects on arachidonic acid metabolites, namely prostaglandins.

The combination of multiple anticytokine approaches to cancer cachexia may represent the most effective treatment. Previous studies demonstrated that the nonsteroidal anti-inflammatory agent, ibuprofen, could downregulate the concentrations of IL-6 and C-reactive protein (positive acute-phase protein) in cancer patients. Therefore, the combination of megestrol acetate and ibuprofen was compared to megestrol and placebo in a 12-week trial of gastrointestinal cancer patients with a median weight loss of 18%.^[19] Most of the patients had advanced pancreatic cancer and were older than 65 years of age. They received megestrol acetate 160 mg 3 times daily with ibuprofen 400 mg 3 times daily or the same dose and a schedule of megestrol with placebo. Baseline anthropometric measurements were performed and repeated at 4-6 weeks and at 12 weeks. Seventy-three patients were included in the study, but the number fell to 41 patients at 4-6 weeks and to 27 patients by week 12 (typical for this type of trial). The intention-to-treat analysis at 12 weeks revealed that only 1 of 38 patients in the megestrol/placebo group gained at least 2 kg vs 9 of 35 patients in the megestrol/ibuprofen group (P < .01). Complications of the trial included venous thrombosis and upper gastrointestinal bleeding, with similar patient numbers in both groups. Many of the patients in the trial also had ascites that may have affected the weight gain observed in the megestrol/ibuprofen group. Notably, the patients in the megestrol/ibuprofen group who gained weight also had an improvement in their quality-of-life scores. This is one of the first trials to combine multiple anticytokine agents to treat cancer cachexia, and it is hoped that further research efforts will be conducted in this area.

The nutritional assessment of cancer patients is highly variable in clinical practice and is commonly not included in the evaluations associated with cancer research trials. Many trials of nutritional support in cancer have failed to enroll severely malnourished patients, specifically those who may have the greatest response to treatment. Additionally, the difficulties in interpreting the results of many cancer trials of nutritional or pharmacologic modulation are obscured by the following factors:

• fluid accumulation in various body compartments

• tumor mass changes

• alterations in hormonal status due to therapy or paraneoplastic syndromes

• effects of therapy for supportive care, including nausea, bowel function, and depression

• effects of anticancer therapies on multisystem organ function

• short-term trials (< 12 weeks)

• high drop-out rates (> 50%)

Table. New Adult Parenteral Multivitamin Formulation Changes

  Parenteral Vitamin Recommendations for Adults (Age >/= 11 yrs) 1975^* 1985^† Fat-soluble Vitamins     Vitamin A 3300 IU 3300 IU Vitamin D 200 IU 200 IU Vitamin E 10 IU 10 IU Vitamin K None 150 mcg Water-soluble Vitamins     Vitamin C 100 mg 200 mg Thiamine (B₁) 3 mg 6 mg Riboflavin (B₂) 3.6 mg 3.6 mg Pyridoxine (B₆) 4 mg 6 mg Cyanocobalamin (B₁₂) 5 mcg 5 mcg Pantothenic acid 15 mg 15 mg Niacin 40 mg 40 mg Biotin 60 mcg 60 mcg Folic acid 400 mcg 600 mcg
* Proposed by the AMA
† Proposed by the US FDA's Division of Metabolic and Endocrine Drug Products and the AMA's Division of Personal and Public Health Policy

References

1. Death associated with thiamine deficient total parenteral nutrition. MMWR Morb Mortal Wkly Rep. 1987;38:38-43.
2. Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition-United States, 1997. MMWR Morb Mortal Wkly Rep. 1997;46:523-528.
3. Alloju M, Ehrinpreis MN. Shortage of intravenous multivitamin solution in the United States. N Engl J Med. 1997;337:54-55.
4. United States Food and Drug Administration. Parenteral multivitamin products; Drugs for human use; Drug efficacy study implementation; Amendment. In: Federal Register 65(77):21200-21201, April 20, 2000.
5. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-1050.
6. Metchnikoff E. The prolongation of life. London (UK): Heinemann; 1907.
7. Fuller R. Probiotics in human medicine. Gut. 1991;32:439-442.
8. Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr. 1995;125:1401-1412.
9. Roberfroid MB. Prebiotics and probiotics: are they functional foods? Am J Clin Nutr. 2000;71(Suppl):1682S-7S.
10. Fuller R. Probiotics in man and animals. A review. J Appl Bacteriol. 1989;66:365-378.
11. Rolfe RD. The role of probiotic cultures in the control of gastrointestinal health. J Nutr. 2000;130:396S-402S.
12. de Roos NM, Katan MB. Effects of probiotic bacteria on diarrhea, lipid metabolism, and carcinogenesis: a review of papers published between 1988 and 1998. Am J Clin Nutr. 2000;71:405-411.
13. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119:305-309.
14. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med. 1980;69:491-497.
15. Barber MD, Ross JA, Fearon KC. Disordered metabolic response with cancer and its management. World J Surg. 2000;24:681-689.
16. Knox LS, Crosby LO, Feurer ID, et al. Energy expenditure in malnourished cancer patients. Ann Surg. 1983;197:152-162.
17. Kotler DP. Cachexia. Ann Intern Med. 2000;133:622-634.
18. Mutlu EA, Mobarhan S. Nutrition in the care of the cancer patient. Nutr Clin Care. 2000;3:3-23.
19. McMillan DC, Wigmore SJ, Fearon KCH, et al. A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. Br J Cancer. 1999;79:495-500.