Standard Total Parenteral Nutrition Research Articles

The clinical and economic value of the dipeptide alanyl-glutamine in total parenteral nutrition of critically ill patients treated in intensive care units in Italy

Introduction: the supplementation of alanyl-glutamine dipeptide in critically ill patients necessitating total parenteral nutrition (TPN) improves clinical outcomes, reducing mortality, infection rate, and shortening ICU hospital lengths of stay (LOS), as compared to standard TPN regimens. Here we present a pharmacoeconomic evaluation of alanyl-glutamine dipeptide in critically ill patients admitted to Italian Intensive Care Units (ICUs). Methods: a Discrete Event Simulation model that incorporates outcomes rates from 200 Italian ICUs for over 60,000 patients, alanyl-glutamine dipeptide efficacy data synthesized by means of a Bayesian Random-Effects meta-analysis, and national cost data has been developed to evaluated the alternatives from the point of view of the hospital. Simulated clinical outcomes are death and infection rates in ICU, death rate in general ward, and hospital LOSs. One-way and probabilistic sensitivity analyses are performed by varying all uncertain parameter values in a plausible range. Results: alanyl-glutamine dipeptide results more effective and less costly than standard TPN: reduced mortality rate (23.55% ± 15.2% vs 34.50% ± 2.06%), infection rate (15.91% ± 3.95% vs 18.97% ± 3.94%), and hospital LOS (25.47 ± 0.26 vs 26.00 ± 0.27 days) come at a lower total cost per patient (23,922 ± 3,249 vs 24,145 ± 3,361 Euro). Treatment cost is completely offset by savings on ICU and antibiotic costs. The cost/effectiveness acceptability curve indicates an estimated 78% probability of alanyl-glutamine dipeptide resulting dominant and a 90% probability of resulting cost/effective for a willingness to pay up to 1,500 Euro for one patient death avoided. Conclusions: alanyl-glutamine dipeptide is expected to improve clinical outcomes and to do so with a concurrent saving for the hospital.

Glutamine: a conditionally essential nutrient or another nutritional puzzle.

Malnutrition and infection are common among patients receiving bone marrow transplant. A recent randomized, double-blind study was conducted to determine whether the addition of glutamine to standard total parenteral nutrition solutions would improve nitrogen retention and reduce hospital morbidity in a group of 45 bone marrow transplant patients. The results showed improved nitrogen balance and reduced incidence of clinical infection in the glutamine-supplemented patients.

Glutamine in parenteral solutions enhances intestinal mucosal immune function in rats.

Biliary secretory immunoglobulin A (sIgA) and proportions of IgA+ plasma cells, helper T cells, and suppressor/cytotoxic T cells in intestinal tissue were lower in rats receiving a standard total parenteral nutrition (TPN) solution than in those receiving TPN enriched with glutamine. Parenteral solutions supplemented with glutamine may preserve the ability of intestinal immune tissue to produce sIgA-synthesizing plasma cells following antigenic stimulation.

Alteration of Canalicular Transporters in a Mouse Model of Total Parenteral Nutrition

Parenteral nutrition-associated liver disease (PNALD) is a major problem with prolonged total parenteral nutrition (TPN) administration. Our laboratory previously demonstrated significant changes in the expression of multidrug resistance genes (MDRs) 1 and 2, hepatocyte transporters, in a TPN mouse model. The present study hypothesized that these changes would lead to functional changes in the liver, and would contribute to the development of liver dysfunction. Mice received either intravenous saline and standard chow or TPN with or without intravenous lipids. Functional assays were performed after 7 days of infusion. TPN with lipids led to a significant increase in serum bile acid levels, consistent with an early state of PNALD. Use of TPN without lipids prevented an elevation in bile acid levels. In both TPN groups, MDR2 expression was significantly (68%) lower than controls and bile phosphatidylcholine content, a functional measure of MDR2, was 40% less than controls. MDR1 expression in the TPN with lipid group was 31% higher than controls, whereas in the TPN without lipids mice there was no significant change. Hepatocyte extrusion of rhodamine dye, a measure of MDR1 function, declined only in the TPN with lipid group. Peroxisome proliferator-activated receptor-alpha expression decreased in both TPN groups. Fenofibrate given with TPN resulted in an increased expression of MDR1 and MDR2, and functionally increased hepatocyte rhodamine extrusion and presence of bile phosphatidylcholine in the TPN with lipid group. The study shows that TPN led to alterations in the function of MDR1- and MDR2-expressed proteins. The changes help in the understanding of the mechanisms leading to PNALD, and suggest that fibrate administration may palliate these changes.

Initiation factors for translation of proteins in the rectus abdominis muscle from patients on overnight standard parenteral nutrition before surgery

Previous studies have provided conflicting conclusions concerning the efficacy of improving protein balance in patients by standard intravenous nutrition [TPN (total parenteral nutrition)], which is either explained by suboptimal nutritional regimens or insensitive clinical methods. The aim of the present study was therefore to evaluate the effects on the initiation of translation of skeletal muscle proteins by standard overnight TPN. A total of 12 patients who underwent standard surgery were included. TPN was provided as an all-in-one treatment by constant infusion [0.16 gN.kg(-1) of body weight.day(-1) (30 kcal.kg(-1) of body weight.day(-1))]. Saline-infused patients served as controls. Rectus abdominis muscle biopsies were taken at the time of the operation. The phosphorylation state of the proteins for initiation of translation was quantified. Plasma glucose, and serum insulin, glycerol, triacylglycerols (triglycerides) and NEFAs (non-esterified fatty acids; 'free fatty acids') were not significantly altered during TPN infusion, whereas total plasma amino acids increased, as shown by increases in methionine, phenylalanine, threonine, alanine, arginine, aspartic acid, glycine and histidine (P<0.05). Overnight TPN increased the formation of active eIF4G-eIF4E (where eIF is eukaryotic-initiation factor) complexes (P<0.05), whereas the inhibitory complex 4E-BP1 (eIF4E-binding protein)-eIF4E was moderately decreased (P<0.06). TPN increased the amount of the most phosphorylated form of 4E-BP1 (P<0.05), and increased the amount (P<0.04) and phosphorylation (P<0.01) of p70(S6K) (70 kDa ribosomal protein S6 kinase). In conclusion, an overnight pre-operative constant infusion of standard TPN altered initiation factor complexes, indicating activation of the initiation of protein translation in rectus abdominis muscle in the presence of increased plasma amino acid levels, but without a concomitant increase in energy substrates and insulin. In contrast with our results from previous studies, the methodology used in the present study appears to be more sensitive in reflecting directional changes in human muscle protein synthesis compared with traditional methods, particularly based on measurements of amino acid flux.

Randomized, Controlled Study of Branched Chain Amino Acid-Enriched Total Parenteral Nutrition in Malnourished Patients with Gastrointestinal Cancer Undergoing Surgery

The objective of this study was to investigate the potential benefit of branched chain amino acid (BCAA)-enriched total parenteral nutrition (TPN) for malnourished surgical patients with gastrointestinal cancer. Sixty-four malnourished patients with gastrointestinal cancer with elective surgical intervention were equally allocated into two groups to receive isonitrogenous and isocaloric TPN. All of them must have received TPN soon after surgery and were subsequently randomized and divided into either BCAA-enriched TPN (30% BCAA; intervention group) or standard TPN (24% BCAA; control group). Patient biochemical data, nutritional parameters, and clinical outcome were collected to analyze the significance of BCAA-enriched TPN. After a period of TPN, laboratory data, including white blood cell (WBC), C-reactive protein (CRP), alkaline phosphatase (ALK-P), and gamma-glutamyltransferase (gamma-GT) levels, were significantly different between these two groups (all P < 0.05). Decreasing white blood cell and C-reactive protein levels were observed in the intervention group that might partially explain the reduced numbers of infectious complications. Furthermore, elevating alkaline phosphatase and gamma-glutamyltransferase levels being also less prominent might indicate a lesser hepatic burden by using BCAA-enriched TPN. The BCAA-enriched TPN can maintain a patient's serum visceral protein (albumin and prealbumin) and positive nitrogen balance better than standard TPN (all P < 0.05). Furthermore, a prominently decreased frequency of postoperative morbidity was also found in the BCAA-enriched TPN group (P = 0.021) despite no difference regarding surgical mortality. Our observations show that BCAA-enriched TPN may be beneficial in improving the nutritional status and reducing postoperative complications for malnourished patients with gastrointestinal cancer undergoing major surgery.

LACK OF ENTERAL NUTRITION BLUNTS EXTRACELLULAR-REGULATED KINASE PHOSPHORYLATION IN GUT-ASSOCIATED LYMPHOID TISSUE

The mitogen-activated protein kinase (MAPK) family (extracellular-regulated kinase [ERK], p38, etc.) of signal transduction proteins includes important intracellular mediators of inflammation, playing critical roles in host defense. Phosphorylations of ERK and p38 are responsible for cell proliferation, cell differentiation, and cell death. We hypothesized that impaired gut-associated lymphoid tissue (GALT) function in the absence of enteral nutrition is associated with reduced MAPK phosphorylation in GALT cells. Fifty-three male Institute of Cancer Research mice were randomized into 3 groups; ad libitum chow, intragastric (i.g.)-TPN, and intravenous (i.v.)-TPN. TPN groups were administered a standard TPN solution. After 5 days of feeding, lymphocytes from Peyer patches (PPs), the lamina propria (LP) cells, and intraepithelial (IE) spaces in the small intestine were isolated. GALT lymphocyte numbers were determined. The lymphocytes were incubated with or without 50 ng/mL of phorbol myristate acetate (PMA) for 15 min, and phosphorylated ERK (p-ERK) and p38 (p-p38) levels were determined using laser scanning cytometry. In PP (GALT inductive site) lymphocytes, p-ERK was increased after PMA in all three groups. However, ERK phosphorylation in GALT effector sites (IE and LP) was enhanced only in the enteral groups. p38 phosphorylation was not increased in any GALT sites, in any of the three groups, in response to PMA. In another set of mice (n = 33), in vitro LP lymphocyte proliferation was assessed with BrdU with or without PMA. Cell proliferation was increased or maintained at high level with PMA in the i.g.-TPN and chow group, but remained low in the i.v.-TPN group. In conclusion, lack of enteral feeding blunts ERK activation and cell proliferation in response to PMA stimulation in GALT effector sites, which may be an important mechanism underlying reduced GALT function. The influence of nutrition on GALT p38 phosphorylation must be assessed with other types and dosages of stimulants.

Effects of glutamine-enriched total parenteral nutrition on acute pancreatitis

This study was performed to determine the effects of glutamine enriched total parenteral nutrition (TPN) on the patients with acute pancreatitis (AP). Forty patients with AP, who had Ranson's score between 2 and 4 received either standard TPN (control group) or TPN with glutamine (treatment group). The patients in the treatment group received TPN containing 0.3 g/kg/days glutamine. At the end of the study, patients were evaluated for nutritional and inflammatory parameters, length of TPN and length of hospital stay. The length of TPN applications were 10.5+/-3.6 days and 11.6+/-2.5 days, and the length of hospital stays were 14.2+/-4.4 and 16.4+/-3.9 days for the treatment and control groups (NS), and the complication rates in the treatment and control groups were 10 and 40%, respectively (P<0.05). The transferrin level increased by 11.7% in the group that received glutamine-enriched TPN (P<0.05), whereas the transferrin level decreased by 12.1% in the control group (NS). At the end of the study, slight but not significant changes were determined in both groups in fasting blood sugar, albumin, blood urea nitrogen (BUN), creatinine, total cholesterol concentrations, aspartate aminotransferase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) activities, leukocytes, CD(4), CD(8), serum Zn, Ca and P levels compare to the baseline levels (NS). Significant decreases were determined in serum lipase, amylase activities and C-reactive protein (CRP) levels in both groups (P<0.05). The results of this study have shown that glutamine supplementation to TPN have beneficial effects on the prevention of complications in patients with AP.

Glutamine and recombinant human growth hormone protect intestinal barrier function following portal hypertension surgery

To evaluate the effects of combined treatment of glutamine (Gln) and recombinant human growth hormone(rhGH) on intestinal barrier function following portal hypertension surgery. This study was designed as a prospective, randomized and controlled clinical trial. Forty two patients after portal hypertension surgery were randomly assigned into 2 groups: control group (n = 20) and supplemental group (adding Gln and rhGH, n = 22). Every patient received isocaloric and isonitrogenous standard total parenteral nutrition (TPN) starting 3 d after surgery for 7 d. Blood samples were obtained before surgery and at the 3rd and 10th day postoperatively. Host immunity was evaluated by measuring levels of CD4, CD8, CD4/CD8, IgG, IgM and IgA, and the inflammatory responses were determined by assessing IL-2, TNF-alpha and C-reactive protein (CRP) levels. Intestinal permeability and integrity was evaluated by L/M test and histological examination, respectively. On postoperative d 10, CD4, CD4/CD8, IgG and IL-2 levels in supplemental group were significantly higher than those in control group (33.7 +/- 5.5 vs 31.0 +/- 5.4, P < 0.05, (1.17 +/- 0.32 vs 1.05 +/- 0.15, P < 0.05, 13.94 +/- 1.09 vs 12.33 +/- 1.33, P < 0.05, and 368.12 +/- 59.25 vs 318.12 +/- 45.65, P < 0.05, respectively), whereas the increase in serum TNF-alpha concentration was significantly reduced (41.02 +/- 27.56 vs 160.09 +/- 35.17, P < 0.05). The increase in L/M ratio was significantly lower in the supplemental group than in the control group (0.0166 +/- 0.0017 vs 0.0339 +/- 0.0028, P < 0.05). Moreover, mucosal integrity in the supplemental group was better than in the control group. Postoperative administration of TPN supplemented with Gln and rhGH in patients after portal hypertension surgery improves immune function, modulates inflammatory response, prevents the intestinal mucous membrane from atrophy and preserves intestinal integrity.

Preclinical trial of l-arginine monotherapy alone or with N-acetylcysteine in septic shock*

L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). Laboratory. Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.

Effect of branched chain amino acid enrichment of total parenteral nutrition on nitrogen sparing and clinical outcome of sepsis and trauma: A prospective randomized double blind trial

Administration of extra branched chain amino acids (BCAA) has been associated with a nitrogen sparing effect in septic and traumatized patients. Whether nitrogen sparing is associated with decreased morbidity and mortality rates is unknown. We therefore undertook a prospective, randomized, double blind trial investigating the effects of BCAA enrichment of a total parenteral nutrition (TPN) regimen on nitrogen balance, 3-methylhistidine excretion, morbidity as evidenced by disturbances in organ function, severity of sepsis and mortality. One hundred and one patients entered the study; 52 received a standard TPN solution and 49 a BCAA-enriched solution. Both groups received 30 kcal kg-1 body-weight, 15 per cent fat calories and 0.17 g nitrogen kg-1 body-weight. In the BCAA-enriched group, patients received 0.56 g BCAA kg-1 body-weight (50.2 per cent BCAA). Standard group patients received 0.18 g BCAA kg-1 body-weight (15.6 per cent BCAA). Nitrogen balances and 3-methylhistidine excretion were not significantly different between groups. Although morbidity scores tended to decrease during the study no difference was observed between groups. Mortality (early or late), sepsis or stress-related, did not differ significantly between groups. We were not able to confirm the reported beneficial effects of BCAA-enriched TPN solutions for use in septic and traumatized patients.

The Effect of Dipeptiven in Patients after Allogenic Hematologic Stem Cell Transplantation.

Total parenteral nutrition (TPN) is provided to patients undergoing allogenic hematologic stem cell transplantation (allo-HSCT) to help minimize nutritional consequences of both conditioning regimens as well as complications resulting from the procedure such as GVHD, VOD and so on, and glutamine could to improve the clinical course of patients after transplantation while given with parenteral nutrition as it is considered that it has stimulatory effects on lymphocytes and mucosa cells in vitro. In the study, we investigated the effect of dipeptiven, N(2)-L-Alanyl-L-Glutamine, which has dipeptides as free glutamine is rather unstable and poorly soluble, added to standard TPN preparations on complication and recovery of patients with allo-HSCT. 40 patients who suffered hematologic malignancies and received allo-HSCT were randomly assigned to receive either standard TPN (control group, n=20), or dipeptiven supplemented TPN (DPT group, n=20). The Bu/Cy2 regimen was used in conditioning with Bu (16mg/kg) plus Cy (120mg/kg) and all patients were given mycophenolate mofetil, CsA and MTX to prevent GVHD. The nutritiona support was started about 1 to 12 days after transplantation and 1.5ml/kg.d dipeptiven was added to the DPT group. During the period of nutritiona support, serum albumin, total protein, creatinine, total bilirubin, leukocytes, lymphocytes were monitored, and time to neutrophil engraftment, decrease of body weight, hospital stays, and other data related to hospital infection and acute GVHD were evaluated for all patients. As a result, the levels of serum albumin fell in the two groups on the 7-day, but on the 28-day those in the DPT group returned to normal and were significantly better than those in the control group (P<0.05). The total bilirubin and creatinine concentration did not change much. And lymphocytes of the patients in the DPT group recovered more rapidly than in the control group (P<0.05). There were less cases with clinical infection and microbial colonization in the DPT group than the control group (10 vs 16,11 vs 17, P<0.05). Also days for antibiotic requirements, days of diarrhea, changes of body weight and hospital stays reduced in the DPT group (16.5±10.6d vs 25.4±16.3d, 4.7±4.5d vs 8.2±6.0d, 2.0±2.0kg vs 3.3±1.6kg, 49.2±18.8d vs 58.0±20.2d, P<0.05, respectively). There were no different between the two groups of incidence of acute GVHD. In the conclusion, DPT-supplemented parenteral nutrition was beneficial in allo-HSCT patients for the nutritional status improving, the incidence of infection and damage of intestine, liver diminishing were all reduced, and the incidence of acute GVHD not increasing.

247 Infusion Rate of Glucose is The Major Predictor of Hyperglycemia in Very Premature Infants Receiving Total Parenteral Nutrition

Background: Hyperglycemia occurs frequently in very premature infants receiving total parenteral nutrition (TPN). Commonly, the glucose infusion rates in TPN exceed the patient's glucose needs. In adult intensive care patients, accompanying hyperglycemia was associated with increased mortality. Since premature infants also represent a high-risk population, preventing hyperglycemia while providing sufficient energy intake may likewise reduce the risk of an adverse outcome.Objective: To determine whether hyperglycemia in infants receiving standard TPN is primarily due to differences in their ability to suppress hepatic glucose production when presented with a high rate of exogenous glucose or to failure of the infant's disposal rate to match the intake.Design/Methods: 11 clinically stable infants (962±49 g; 26.7±0.4 wks) were studied on day 4±1 of life while receiving TPN as ordered by the attending physician. Glucose production rate (GPR) was measured during an 8 h period of stable blood glucose using isotope dilution of [6,6–2H2]glucose. Multiple regression analysis was used to determine the effects of infusion rate of glucose, lipids and amino acids, residual GPR, gestational age and birth weight on blood glucose concentration.Results: Range and median (within parenthesis) for each parameter: Blood glucose 5.3–12.6 (7.1) mM; Total glucose appearance rate (Ra) 8.9–13.1 (10.9) mg/kg min of which glucose infusion was 7.3–11.3 (9.5) mg/kg min and residual GPR 0.1–1.5 (1.4) mg/kg min; Infusion rate of lipids was 0.6–2.7 (2.1) mg/kg min and of amino acids 1.6–2.2 (2.0) mg/kg min. Glucose Ra explained 58% of the variation in blood glucose concentration (p<0.007), of which the glucose infusion rate accounted for the major part, 49% (p<0.02) and GPR for only 9% (p<0.05); gestational age explained 9% while infusion rates of amino acids and lipids, and birth weight did not affect blood glucose concentration. GPR was suppressed by 80% (assuming a normal glucose turnover rate of 6 mg/kg min).Conclusion: In premature infants receiving TPN, the infusion rate of glucose is the strongest predictor of hyperglycemia, while residual GPR and gestational age have marginal impact. A potential clinical implication of these results is that a reduction of the glucose infusion rate while maintaining adequate supply of lipids and amino acids will reduce the incidence of hyperglycemia without compromising energy and protein balance. Grants: NIHRO1-HD37957–05; GCRCNIHHO1-RR-001888.

L-arginine-enriched parenteral nutrition affects lymphocyte phenotypes of gut-associated lymphoid tissue.

Experimentally, total parenteral nutrition (TPN) diminishes gut-associated lymphoid tissue (GALT) cell numbers and function. Although glutamine supplementation is known to reverse TPN-induced changes in GALT, effects of another conditionally essential amino acid, L-arginine (ARG), on GALT remain unclear. Twenty-two male Institute of Cancer Research mice were randomized to standard TPN (0.3% arginine, STD-total parenteral nutrition) or 1% ARG-enriched TPN (ARG-total parenteral nutrition). After 5 days of feeding, lymphocytes were harvested from Peyer's patches (PP), the lamina propria, and intraepithelial (IE) spaces of the small intestine to determine cell yields. Lymphocyte phenotypes (alphabetaTCR, gammadeltaTCR, CD4, CD8, and B220 as a B cell marker) were determined using flow cytometry. IgA levels in washings of the small intestine, upper respiratory tract, and lungs were measured with ELISA. ARG-total parenteral nutrition did not affect lymphocyte yields. The percentages of CD4+ cells in PP and IE, and alphabetaTCR+ cells in PP, were significantly higher in the ARG-total parenteral nutrition than in the STD-total parenteral nutrition mice, without marked differences in other phenotypes examined. There were no significant differences in intestinal and respiratory tract IgA levels between the 2 groups of mice. One percent ARG supplementation of TPN does not improve GALT cell number or mucosal IgA level but benefits to increase CD4+ cell percentages in GALT.

Effects of lipid administration on liver apoptotic signals in a mouse model of total parenteral nutrition (TPN).

Lipids are an important component of total parenteral nutrition (TPN), contributing the largest caloric load per volume of solution and providing essential fatty acids necessary for survival. However, lipids are known to be causative factors in oxidative stress, which are expressed via the Bcl-2 family of proteins and/or Fas-mediated apoptosis in several tissues. Interestingly, we have recently observed an increase in hepatocyte apoptosis with administration of TPN. To address the mechanism of this apoptosis, we investigated the effects of parenteral lipid administration on apoptotic signaling in a mouse model. C57BL/6J male mice received physiologic saline and standard chow (control) or standard TPN solution with (TPN+L) or without lipid (TPN-L) emulsion. After 7 days of infusion, apoptosis increased in the TPN+L at a significantly higher rate compared with control and TPN-L groups ( p<0.05). Both TPN, with and without lipids, suppressed the pro-apoptotic signals Bid and Bcl-xs ( p<0.05). In contrast, TPN with lipid increased the expression of Fas and both the pro-apoptotic factor Bad and the anti-apoptotic factor Bcl-xl ( p<0.05). These changes may contribute to TPN-induced hepatocyte injury (apoptosis) or suppress the ability of liver hepatocytes to regenerate.

Hepatic P-glycoprotein changes with total parenteral nutrition administration.

The mechanism(s) responsible for the development of parenteral nutrition-associated liver disease (PNALD) is unknown. Recently, a number of bile canalicular transport proteins have been identified that transport bile components out of hepatocytes. One group of these genes, multidrug resistance 1 (mdr1) and mdr2, encode P-glycoproteins. Mice lacking mdr2 expression develop liver disease that appears similar to PNALD. This study investigated the alteration in the expression of these transport proteins during the administration of total parenteral nutrition (TPN). Mice received either physiologic saline and standard chow or TPN. Mice were sacrificed on day 7, and hepatic DNA and RNA content, mRNA expression, and levels of mdr1 and mdr2 proteins were measured. TPN administration led to a significant (p < .05) decline in mdr2 mRNA expression and an increase in mdr1 mRNA expression. Mdr2 protein expression declined by 66% in the TPN-treated group, and mdr1 protein expression significantly increased by 58%. Histology and biochemical parameters showed no evidence of liver injury. Serum bile acid levels were elevated in the TPN group, suggesting the development of early cholestasis. The decline in mdr2 and rise in mdr1 mRNA and protein expression with TPN administration occurred before the development of liver injury but during an early state of cholestasis. This suggests that alterations in mdr gene expression may be a causative factor in the development of PNALD.

L-Alanyl- l-glutamine-supplemented parenteral nutrition improves infectious morbidity in secondary peritonitis

Background & aims: A growing number of randomized clinical trials suggest that glutamine (Gln) supplementation may be beneficial in a selected group of patients and conditions. However, the effects of Gln-enriched total parenteral nutrition (TPN) on recovery from acute intra-abdominal infection have not been thoroughly investigated. Therefore, the aim of this study was to investigate whether the provision of Gln-enriched TPN after surgical and medical treatment of secondary peritonitis improves infectious morbidity. Methods: Thirty-three patients with secondary peritonitis were randomly assigned to receive either standard ( n=16) TPN or l-alanyl- l-glutamine-supplemented ( n=17) TPN, after medical and surgical treatment of the infectious focus. The two TPN formulae were isonitrogenous and isocaloric, which commenced the morning after surgery and ran continuously for 10 consecutive days. The control group received standard TPN, while the treatment group was given l-alanyl- l-glutamine, 0.40 g/kg/d (Dipeptiven, ® Fresenius Kabi, Bad Homburg, Germany). Infectious morbidity, nitrogen balance, leukocytes, lymphocytes, subpopulations CD 4 and CD 8, Immunoglobulin A (IgA), total proteins, albumin, hospital and intensive care unit (ICU) stays, and mortality were evaluated. Statistical analysis included one-way ANOVA, the unpaired Student's t-test, the Mann–Whitney U-test, χ 2 test, or Fisher's exact test. Results: Patients in both groups were comparable prior to the operation. Nitrogen balance and the levels of albumin and IgA were significantly better than those in the control group. Also, a significant reduction in the infectious morbidity was found in the Gln-treated group. Lymphocyte counts as well as subpopulations CD 4 and CD 8, and proteins showed a propensity to improvement and a tendency to reduced rates of mortality were observed when comparing the groups. Hospital and ICU stays were similar. Conclusion: l-alanyl- l-glutamine-supplemented TPN improved the infectious morbidity of patients with secondary peritonitis. Gln supplementation to parenteral nutrition may be an alternative for enhancing host defenses and improving infectious morbidity.

Effect of glutamine dipeptide on hepatic regeneration in partially hepatectomized malnourished rats

Objective Glutamine promotes hepatic regeneration in nourished (N) rats. The aim of the present study was to evaluate the effects of glutamine-enriched total parenteral nutrition (TPN) on liver regeneration in malnourished (MN) rats. Methods Seventy-two male Wistar rats (≅270 g) were assigned to one of two groups: N and MN. Each group was then subdivided into three groups: the first underwent partial hepatectomy (PH) and received standard TPN enriched with l-alanyl- l-glutamine (Ala-Gln); the second also underwent PH and received standard TPN, but enriched with a solution containing proline and alanine (Ala-Pro); and the third underwent no surgical procedure (control group). All experimental groups received isocaloric (188 kcal · kg −1 · d −1) and isonitrogenous (1.12 g of nitrogen · kg −1 · d −1) TPN for 96 h. All animals were injected with bromodeoxyuridine 2 h before death. The hepatic regeneration index (HRI), hepatic growth percentage (HG) and hepatic morphology were analyzed. Results In MN rats, HRI and HG were higher with glutamine enrichment (HRI = 81 and HG = 190) than with proline-containing TPN (HRI = 66 and HG = 154; P < 0.05) and HRI was 100 times higher in animals that underwent PH than in control animals. Morphologic analysis of hepatic tissue showed no difference among the six groups. Conclusion Glutamine-enriched TPN promoted growth of the remnant liver in MN rats after PH, maintained cellular proliferation in the various experimental groups after surgery, and maintained hepatic morphology of MN rats after surgery.

The role of parenteral lipids in supporting gluconeogenesis in very premature infants.

We have previously demonstrated that very premature infants receiving glucose at 17 micromol/kg min plus appropriate supply of parenteral lipids (Intralipid) and amino acids (TrophAmine) maintained normoglycemia by glucose produced primarily via gluconeogenesis. The present study addressed the individual roles of parenteral lipids and amino acids in supporting gluconeogenesis. Fourteen premature infants (993 +/- 36 g 27 +/- 1 wk) (mean +/- SE) were studied for 8 h on d 5 +/- 1 of life. All infants were receiving standard TPN prior to the study. At start of study, the glucose infusion rate was decreased to approximately 17 micromol/kg min and either Intralipid (g + AA; n = 8) or TrophAmine (g + IL; n = 6) was discontinued. Data from 14 previously studied infants receiving glucose (approximately 17 micromol/kg min) + TrophAmine + Intralipid (g + AA + IL) are included for comparison. Gluconeogenesis was measured by [U-13 C]glucose, (g + AA) and (8 infants of the g + AA + IL group) or [2-13C]glycerol, (g + IL) and (6 infants of the g + AA + IL group). Infants studied by the same method were compared. Withdrawal of Intralipid resulted in decreased gluconeogenesis, 6.3 +/- 0.9 (g +AA) vs. 8.4 +/- 0.7 micromol/kg min (g + AA + IL) (p = 0.03). Withdrawal of TrophAmine affected neither total gluconeogenesis, 7.5 +/- 0.8 vs. 7.9 +/- 0.9 micromol/kg min nor gluconeogenesis from glycerol, 4.4 +/- 0.6 vs. 4.9 +/- 0.7 micromol/kg min (g+ IL and g + AA + IL groups, respectively). In conclusion, in parenterally fed very premature infants, lipids play a primary role in supporting gluconeogenesis.

Glutamine infusion during ischemia is detrimental in a murine gut ischemia/reperfusion model.

Gut ischemia/reperfusion (I/R) frequently occurs in clinical settings as a result of disproportionate splanchnic hypoperfusion during shock. Glutamine (GLN) supplementation of total parenteral nutrition (TPN) before gut I/R improves survival after gut I/R compared with standard TPN. However, it is unknown whether GLN treatment after the occurrence of the insult is beneficial or not. The aims of this study were to examine effects of GLN infusion during gut ischemia on survival, myeloid cell (neutrophils + monocytes) activation, and vascular permeability in organs. Male Institute of Cancer Research (ICR) mice were randomized to control and GLN groups. After IV cannulation, mice underwent 90 (experiments 1 and 2) or 60 (experiment 3) minutes of gut I/R. Control mice received normal saline infusion at 1 mL/h for 60 minutes during ischemia, whereas the GLN group was given 3% GLN solution. In experiment 1, survival rates were monitored for 72 hours (n = 25). In experiment 2, peripheral blood was obtained at 2 or 4 hours after reperfusion (n = 17). Reactive oxygen intermediate (ROI) production by myeloid cells was determined by flow cytometry using dihydrorhodamine 123 with or without phorbol myristate acetate stimulation. Expression of CD11a and CD11b on myeloid cells was also measured. Myeloperoxidase (MPO) activity in the lung was evaluated. In experiment 3, vascular permeability in organs was measured using Evans blue at 2 or 4 hours. In experiment 1, survival time in the GLN group was significantly reduced compared with the control group (p = .02, log-rank test). The survival rates were 92% (12/13) and 42% (5/12) for the control and GLN groups at 12 hours (p = .01) and 38% (5/13) and 0% (0/12) at 48 hours (p = .02), respectively. In experiment 2, ROI production was significantly higher in the GLN group than in the control group after PMA stimulation both at 2 and 4 hours. CD11b expression was significantly higher in the GLN group than in the control group at 4 hours. There was no difference in pulmonary MPO activity at either time point. In experiment 3, GLN infusion significantly increased hepatic vascular permeability compared with saline infusion at 4 hours. GLN infusion during ischemia is detrimental for survival after gut I/R. A possible mechanism is excessive priming of myeloid cells caused by GLN infusion. Timing of GLN administration is critical for outcome after gut ischemic insult.