A randomized, placebo-controlled trial of combined insulin-like growth factor I and low dose growth hormone therapy for wasting associated with human immunodeficiency virus infection.

Loss of body mass, or wasting, is a major cause of morbidity and a contributor to mortality in human immunodeficiency virus-1 (HIV-1) infection. Dietary supplements and appetite adjuvants have had limited effectiveness in treating this condition. GH and insulin-like growth factor I (IGF-I) have been shown to be anabolic in many catabolic conditions, and limited data suggest similar efficacy in HIV wasting. In addition, it appears that GH and IGF-I may have complementary anabolic effects with opposing glucoregulatory effects. We report results from a 12-week randomized, placebo-controlled trial of combination recombinant human GH (rhGH; Nutropin; 0.34 mg, sc, twice daily) and rhIGF-I (5.0 mg, sc, twice daily) in individuals with HIV wasting and without active opportunistic infection, cancer, or gastrointestinal disease. A total of 142 subjects (140 males and 2 females) were randomized using a 2:1, double blind treatment scheme and assigned to receive either active treatment or placebo injections. Eighty subjects completed the 12-week protocol. Nutritional intake and demographic and clinical characteristics did not differ between the groups at any study time point. At 3 weeks, the treatment group had a significantly larger weight increase (P = 0.0003), but this difference was not observed at any later time point. Similarly, fat-free mass, calculated from skinfold measurements, increased transiently in the treatment group at 6 weeks (P = 0.002). No significant differences in isokinetic muscle strength or endurance testing or in quality of life were observed between the groups. Resting heart rate was significantly higher in the treatment group at each time point post-baseline. GH and IGF-binding protein-3 levels did not change; however, IGF-I levels were higher in the treatment group at 6 and 12 weeks. There were no significant between-group differences in any of the measured biochemical or immunological parameters. rhGH plus rhIGF-I treatment was associated with an increased incidence of peripheral edema and other side-effects, possibly related to fluid retention. We conclude that the combination of rhIGF-I and low dose rhGH used in this study had no significant anabolic effect in HIV wasting.

The mucosa-associated lymphoid tissue structure, function, and derangements.

Nearly 50% of the immune cells in the body lie just beneath the moist mucosal surfaces at intestinal and extra-intestinal sites. The study of this mucosal immune system in response to shock and to route and type of nutrition provides a cogent explanation for the reduced incidence of pneumonia with enteral feeding. Changes in immune cell mass and function are associated with deterioration of previously established immunity at mucosal surfaces, especially the respiratory tract. By understanding the mechanisms involved in this breakdown, therapeutic strategies can be developed to reduce septic complications in critical illness.

TPN decreases IL-4 and IL-10 mRNA expression in lipopolysaccharide stimulated intestinal lamina propria cells but glutamine supplementation preserves the expression.

Total parenteral nutrition (TPN) decreases intestinal IgA and levels of Th2 cytokines, interleukin (IL)-4, and IL-10 within the supernatants of intestinal homogenates. These cytokines are known to stimulate IgA production in vitro by cells of the gut-associated lymphoid tissue (GALT). Glutamine (GLN) supplementation of TPN normalizes GALT mass and cytokine levels. Because intestinal homogenates contain mucosa which itself is a source of cytokines, it was unclear whether cytokines change within the GALT itself. This study investigates dietary effects on IL-4 and IL-10 cytokine mRNA expression within isolated GALT lamina propria cells after lipopolysaccharide (LPS) stimulation. Prospective randomized experimental trials were used in this study. Fifty-nine mice were randomized to chow, intravenous TPN (IV-TPN), intragastric TPN (IG-TPN), complex enteral diet (CED), or 2% GLN-supplemented TPN (GLN-TPN). In experiment 1, animals were fed chow, IV-TPN, IG-TPN, or CED for 5 days and received intraperitoneal LPS (100 microg/kg BW), and then were sacrificed 1 h later. Intestine was harvested for GALT lamina propria. Total RNA was extracted from lamina propria cells and cytokine mRNA for IL-4, and IL-10 was measured by reverse transcriptase polymerase chain reaction. IgA levels of intestinal washing were also measured with ELISA. In experiment 2, mRNA for IL-4 and IL-10, and intestinal IgA levels were measured in mice fed chow, IV-TPN, or GLN-TPN as in experiment 1. Both IL-4 and IL-10 mRNA expression decreased significantly in IV-TPN mice compared to chow or CED feeding. IG-TPN resulted in IL-10 mRNA expression significantly lower than chow or CED but significantly better than IV-TPN. GLN preserved IL-4 and IL-10 mRNA levels, which correlated with intestinal IgA levels. Route and type of nutrition as well as GLN influence message for the Th2 type IgA-stimulating cytokines, IL-4 and IL-10, within the primary site of GALT IgA production, the lamina propria.

Modulation of organ ICAM-1 expression during IV-TPN with glutamine and bombesin.

The gut primes neutrophils (PMNs) during injury, which can then induce distant organ damage after a second insult. ICAM-1 is an important adhesion molecule in PMN attachment to the vascular endothelium. Parenteral nutrition (TPN) decreases gut levels of interleukin (IL)-4 and IL-10, two cytokines that are normal inhibitors of ICAM-1 expression. TPN also increases gut ICAM-1 expression and PMN accumulation. Since glutamine (GLN) and bombesin (BBS) prevent TPN-associated impairment of mucosal immunity, we hypothesized that GLN and BBS would modulate organ ICAM-1 expression in association with normalization of IL-4 and IL-10 levels. Forty-four mice were fed chow, TPN, or GLN-TPN (isonitrogenous 2% GLN-enriched TPN). After 5 days of diets, ICAM-1 expression was quantified in organs using the dual radiolabeled monoclonal antibody technique. In the next experiment, 29 mice were fed chow, TPN, or BBS-TPN (BBS 15 microg/kg TID) for 5 days to measure organ ICAM-1 expression. Total IL-4 and IL-10 levels were measured with ELISA from intestinal homogenates of another set of 52 mice fed chow, TPN, GLN-TPN, or BBS-TPN. TPN significantly increased ICAM-1 expression in the lung, kidney, and intestine compared with chow mice. GLN-TPN decreased intestinal, but not lung, ICAM-1 expression, while BBS-TPN reduced pulmonary, but not gut, ICAM-1 levels. GLN- and BBS-TPN returned gut IL-4 levels to normal, but failed to increase IL-10 levels. GLN and BBS had different effects on organ ICAM-1 expression induced by lack of enteral nutrition. Mechanisms other than recovery of IL-4 alone may be responsible for gut ICAM-1 expression.

Occult gastrointestinal malignancies producing metastatic Clostridium septicum infections in diabetic patients.

BACKGROUND: Clostridial soft-tissue infections usually occur from traumatic injury but may be related to unrecognized gastrointestinal malignancy. Overwhelming sepsis with Clostridium septicum developed in five diabetic patients within 24 hours of onset of disease, and their course is reviewed. METHODS: The personal experience of the author in four cases is reviewed. RESULTS: Patients were seen within 12 to 24 hours of the onset of the disease with painful, rapidly spreading, gas-producing infection of the lower extremity (three patients), upper extremity (one patient), or pelvis (one patient), with severe sepsis in four of five patients. Three of the five patients had pertinent past histories that should have led to the prevention of the disease. CONCLUSIONS: Urgent laparotomy should be performed in otherwise healthy diabetic patients who had rapidly progressive, necrotizing, gas-producing infections with no obvious source. Metastatic spread can recur if the focus is not eradicated. All diabetic patients with guaiac-positive stools should have a gastrointestinal evaluation, including colonoscopy if barium enema is normal.

Effect of glutamine-enriched total parenteral nutrition on small intestinal gut-associated lymphoid tissue and upper respiratory tract immunity.

BACKGROUND: Our prior work shows that total parenteral nutrition (TPN) causes small intestinal gut-associated lymphoid tissue (GALT) atrophy, lowers small intestinal immunoglobulin A (IgA) levels, and impairs secretory IgA-mediated mucosal immunity of the upper respiratory tract. These experiments examine whether an isonitrogenous 2% glutamine-enriched TPN solution prevents these changes. METHODS: Institute of Cancer Research mice were randomized to chow (chow), intravenous feeding of a TPN solution (TPN), or glutamine-enriched TPN (glutamine) groups. After mice were fed for 5 days, lymphocytes were isolated from Peyer's patches, the intraepithelial layer, and lamina propria to determine cell yields and phenotypes. Total small intestinal IgA levels were analyzed by means of enzyme-linked immunosorbent assay. In a second series of experiments, mice underwent intranasal inoculation with H1N1 virus to establish immunity. After 3 weeks mice were randomized to chow, TPN, or glutamine groups. After feeding for 5 days, mice were rechallenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS: Total lymphocyte yield in the Peyer's patches, the intraepithelial layer, and lamina propria, small intestinal IgA levels, and the CD4+/CD8+ ratio in the lamina propria decreased with TPN but remained normal with glutamine. On rechallenge, 87% of the mice in the TPN group shed virus in nasal secretions, whereas only 38% of the glutamine-treated group (p < 0.05 versus TPN) and 7.1% of the chow group (p < 0.002 versus TPN) were virus positive. CONCLUSIONS: Isonitrogenous supplementation of TPN with 2% glutamine improves IgA-mediated protection in the upper respiratory tract and normalizes GALT populations.

High molecular weight dextran--effect on adhesion formation and peritonitis in rats.

To evaluate the effect of 32% dextran 70 instillation on intra-abdominal adhesion formation and intestinal leaks, 100 animals were prospectively, randomly, and blindly treated with a sham laparotomy (n = 10), sham plus 5 ml dextran (10), intestinal abrasion plus 2 ml (20) or 5 ml (20) of dextran or saline, or intestinal division and anastomosis plus 2 ml (20) or 5 ml (20) of dextran or saline. Autopsies were performed on the animals without knowledge of treatment group at the time of death or sacrifice at 2 weeks. Adhesions were graded 0 to 3, anastomoses were examined for leaks, and the peritoneal cavity was searched for abscesses or peritonitis. Anastomosis produced more severe adhesions than abrasion. Dextran significantly (P greater than 0.01) reduced adhesion formation but resulted in peritonitis (5/40) rather than abscess (7/40) as seen with saline.

Visceral protein response to enteral versus parenteral nutrition and sepsis in patients with trauma.

BACKGROUND: Sepsis and the route of nutrient administration are clearly related to visceral protein levels; however, the mechanisms and amount of influence are not completely defined. METHODS: Constitutive and acute-phase protein levels were measured on days 1, 4, 7, and 10 in 68 severely injured patients with abdominal trauma indexes of 15 or more randomized to enteral or parenteral feeding. Groups were matched for age, abdominal trauma index, injury severity score, and length of stay. RESULTS: Significantly higher levels of constitutive proteins and lower levels of acute-phase proteins were found in patients randomized to enteral feeding. Although some "hepatic protein reprioritization" appeared to be caused by nutrient route, this appeared only in the less severely injured patients. A more important factor in visceral protein levels is a reduction in septic morbidity associated with enteral feeding. CONCLUSIONS: Enteral feeding produces greater increase in constitutive proteins and greater decreases in acute-phase proteins after severe trauma primarily caused by reduced septic morbidity with enteral feeding.

Duration of antibiotic therapy for penetrating abdominal trauma: a prospective trial.

BACKGROUND: The optimal duration of antibiotic use in penetrating abdominal trauma is incompletely defined. It is generally accepted that short-term antibiotics are appropriate for low-risk wounds. However, with colon injury and significant degree of injury, abdominal trauma index (ATI) more than 25, concern exists that short-term treatment is not adequate. METHODS: The study was a prospective double-blind trial of 24-hour treatment (cefoxitin or cefotetan) compared with 5-day treatment in 515 patients. Major abdominal infections (MAI) included abscess, necrotizing fasciitis, and diffuse peritonitis. RESULTS: MAI occurred in 8% of those patients with 1-day therapy and 10% with 5-day therapy. Subgroup analysis of high-risk groups (colon wounds and ATI of more than 25) showed the following MAI rates: colon, 1-day therapy, 14%; 5-day therapy, 15%; ATI of more than 25, 1-day therapy, 17%; 5-day therapy, 30%. CONCLUSIONS: Regardless of contamination and degree of injury, 24-hour antibiotic therapy is satisfactory for all penetrating abdominal trauma.

Effect of nutritional status on organic anion clearance by the swine liver.

Hepatic dysfunction follows a wide range of insults. Impaired excretion of organic dyes such as bilirubin often occurs before other obvious clinical defects in metabolic processes. Indocyanine green (ICG) is excreted through pathways similar to those of bilirubin. To determine the effectiveness of ICG as a marker of hepatic dysfunction related to clinical malnutrition, pigs received 5 mg/kg ICG with simultaneous sampling from the hepatic vein, pulmonary artery, and aorta over 3 hours. Group I remained well nourished, group II was fasted to a weight loss equal to 20% of initial body weight, and group III was fasted to a 20% weight loss and then refed until the animals regained their initial weight. Both systemic and intrinsic hepatic clearance were depressed significantly with fasting but returned above baseline after refeeding. No significant difference appeared between systemic and intrinsic hepatic clearance. Extraction ratios were low in all groups. In outbred swine, ICG clearance reflects the function of hepatic organic anion excretion in vivo, and venous sampling reflects intrinsic hepatic clearance. The impairment of the carrier-mediated transport system is reversible with refeeding.

Effect of route of nutrition on recovery of hepatic organic anion clearance after fasting.

BACKGROUND: Previous work documented a 40% depression of hepatic indocyanine green (ICG) clearance (ClICG) in pigs fasted to 20% weight loss, with return to normal within 12 days of food refeeding. ClICG in pigs is insensitive to changes in hepatic blood flow but very sensitive to changes in hepatic function (HF). Serial ClICG determinations were performed to quantify the effect of route of nutrient delivery on recovery of HF. METHODS: Fourteen pigs were fasted to 20% weight loss (12.8 days average) with both gastrostomy and intravenous catheters placed in each animal midway through the fast. ClICG was measured before fast, after fast, and after 12 days refeeding through the enteral or parenteral route at 125 kcal/kg/day with isonitrogenous, isocaloric diets containing 9% fat. Urine and stool were analyzed for total nitrogen. RESULTS: No significant differences appeared between groups in nitrogen output during fasting (4.5 +/- 1.2 gm/kg enteral, 4.6 +/- 1.2 gm/kg parenteral), in nitrogen intake (800 +/- 19 mg/kg/day enteral, 810 +/- 10 mg/kg/day parenteral), or in before or after fast ClICG, but enteral feeding produced more positive nitrogen balance. ClICG improved significantly with enteral but not with parenteral feeding. CONCLUSIONS: Enteral feeding produces faster nitrogen accrual and reverses the depression of major pathways of bilirubin and organic anion excretion associated with malnutrition. Parenteral feeding failed to improve organic anion clearance despite weight gain.

Use of selected visceral protein measurements in the comparison of branched-chain amino acids with standard amino acids in parenteral nutrition support of injured patients.

Twenty injured patients in the intensive care unit were randomized to receive parenteral nutrition with either 21% (STD) or 46% (HBC) branched-chain amino acids to compare the response of nitrogen balance (NB), somatomedin-C/insulin-like growth factor I (SMC), circulating fibronectin (FBN), and prealbumin (PA). NB was measured and serum collected for SMC, FBN, and PA on days 1, 4, 7, 14, and 21 of nutritional intervention. The treatment groups did not differ significantly for age, weight, injury severity score, trauma score, Apache II score, acute-phase protein concentrations, or type of injury. Comparison of baseline measurements revealed no significant differences in SMC, FBN, or PA. Both groups received similar doses of nonprotein energy and nitrogen. Baseline urea nitrogen excretion was slightly higher in the STD group (216 +/- 55 vs 268 +/- 54 mg/kg/day p = 0.049). Although NB was significantly improved over baseline during subsequent study days, there were no differences between groups after the day-1 measurement. SMC increased significantly from baseline on day 4 in the STD group, on day 7 in the HBC group, and on days 14 and 21 in both groups. There was no significant difference in SMC concentrations between groups on any day. Each group demonstrated a significant increase in PA from baseline on days 7, 14, and 21; however, no difference was seen when groups were compared. FBN increased significantly from baseline on day 14 in the HBC group and on days 7 and 14 in the STD group. FBN measurements were significantly different between groups on day 14 (STD, 179 +/- 71 vs HBC, 229 +/- 59 micrograms/ml; p less than 0.05). NB, PA, SMC, and FBN improve significantly during parenteral nutrition of traumatized patients. With the measured variables, there appears to be no significant difference between STD or HBC amino acids when used as part of parenteral nutrition in injured patients.

The gut's role in metabolism, mucosal barrier function, and gut immunology.

The gastrointestinal tract functions not only to absorb nutrients, it also plays an important immunologic role during health and critical illness. Under experimental and certain clinical conditions, stimulating the gut attentuates the stress response and avoids mucosal atrophy and increases permeability. Gut stimulation prevents atrophy of the gut-associated lymphoid tissue, the body's major defender of moist mucosal surfaces. A better understanding of gut function and improved nutrient delivery has clinical implications in the treatment of critically ill patients.

A temporal study of TPN-induced changes in gut-associated lymphoid tissue and mucosal immunity.

BACKGROUND: Total parenteral nutrition (TPN) is associated with decreases in small-intestinal gut-associated lymphoid tissue (GALT) T cells, B cells, and IgA levels and impairs IgA-mediated defenses in the respiratory tract. The impaired respiratory tract defenses are speculated to be due to reduced respiratory tract IgA levels. OBJECTIVES: To determine the time course of GALT cell reductions and document any changes in respiratory tract IgA levels in mice receiving TPN. DESIGN: Prospective randomized trial. SETTING: Animal research laboratory. MATERIALS: Thirty-five male ICR mice weighing 25 to 35 g. INTERVENTIONS: Mice underwent cannulation with intravenous catheters and received chow for 2 days followed by TPN for 0 (n=6), 1 (n=6), 2 (n=6), 3 (n=6), 4 (n=6), or 5 (n=5) days. Mice were killed after receiving TPN their respective number of days. The small intestine was harvested, and washings were obtained from the small intestine and the respiratory tract. Lymphocytes and IgA levels were analyzed by flow cytometry and enzyme-linked immunosorbent assay, respectively. MAIN OUTCOME MEASURES: Lymphocyte yields from Peyer patches, intraepithelial spaces, and the lamina propria; IgA levels from the small intestine and the respiratory tract. RESULTS: T- and B-cell yields in the Peyer patches and lamina propria were significantly reduced by day 2 (P<.05) and thereafter compared with day 0. The lamina propria CD4+/CD8+ ratio declined significantly by day 4 (P<.05) compared with day 0. Small-intestinal and respiratory tract IgA levels were significantly diminished by day 3 (P<.05) and thereafter compared with day 0. CONCLUSION: Total parenteral nutrition produces rapid changes in GALT cell profiles and reduces respiratory tract IgA levels consistent with the impairment of respiratory IgA-mediated defenses.

Determinants of survival after vena caval injury. Analysis of a 14-year experience.

The records of 70 patients with vena caval injuries who were treated from 1970 through 1983 were reviewed to define factors determining patient survival. Fifty-two percent of patients survived, with the highest mortality in patients with blunt or shotgun injuries. The primary determinants of survival were the mechanism and type of injury, the initial BP, the hemodynamic response to fluid resuscitation, the location of the vena caval injury, the presence of multiple other vascular and solid organ injuries.

Effect of bombesin on impairment of upper respiratory tract immunity induced by total parenteral nutrition.

OBJECTIVE: To determine the effect of the neuropeptide bombesin on total parenteral nutrition-induced impairment of upper respiratory tract immunity. DESIGN: Randomized, controlled trial. PARTICIPANTS: Thirty-six adult male Institute for Cancer Research mice weighing 25 to 35 g. INTERVENTIONS: Mice were inoculated intranasally with H1N1 virus. At 3 weeks, mice were randomized to receive chow plus intravenous saline (n = 12), intravenous total parenteral nutrition (n = 12), or intravenous total parenteral nutrition plus bombesin (n = 12) administered 3 times daily at 15 micrograms/kg. After 5 days, mice were rechallenged with intranasal virus and killed at 40 hours to determine viral shedding from the respiratory tract; normal convalescent mice do not shed virus because of intact IgA-mediated mechanisms. MAIN OUTCOME MEASURES: Viral shedding was determined by collection of nasal secretions. Samples were diluted and incubated with a suspension of Madin-Darby canine kidney cells. Viral growth was determined by hemagglutination. RESULTS: Body weight was similar between the total parenteral nutrition and bombesin groups; however, both were significantly lower than that in the chow group (P < .05). After 6 days of feeding, no mice in the chow group shed virus, compared with 6 (50%) of the mice in the total parenteral nutrition group. Of the mice in the bombesin group, only 1 was positive for viral shedding. The total parenteral nutrition group showed increased viral shedding compared with both the chow group (P < .01) and the bombesin group (P < .05). CONCLUSIONS: Exogenous administration of bombesin reversed the total parenteral nutrition-associated impairment of upper respiratory tract immunity to an IgA-mediated infectious challenge. These observations support the concept of a common mucosal immune system, since neuropeptides are endogenous to the gastrointestinal and respiratory tracts. Hormonal modulation of immunity is a promising avenue of treatment for patients who require total parenteral nutrition.

Bombesin affects mucosal immunity and gut-associated lymphoid tissue in intravenously fed mice.

BACKGROUND: Our prior studies show that intravenous (IV) total parenteral nutrition (TPN) produces atrophy of the small intestine-related gut-associated lymphoid tissue and significant decreases in intestinal IgA levels, the major system of mucosal immunity. Others have noted increased small intestinal permeability, bacterial adherence and translocation, and decreased IgA levels in TPN-fed animals. Bombesin, a neuropeptide, may play a regulatory role in mucosal immunity. It is not clear whether bombesin attenuates the TPN-associated gut-associated lymphoid tissue atrophy. OBJECTIVE: To examine the effect of bombesin on gut-associated lymphoid tissue integrity and function during IV TPN feeding. DESIGN: Randomized animal study. SETTING: A university laboratory. MATERIALS AND METHODS: Male ICR mice weighing 25 to 30 g were randomized to chow plus IV saline solution (n = 12), IV TPN (n = 12), or IV TPN plus bombesin (15 micrograms/kg, administered intramuscularly three times a day) (n = 12). Animals were killed after 5 days of receiving the experimental diet. Total small intestinal IgA level was quantified by enzyme-linked immunosorbent assay. Lymphocytes were isolated from Peyer's patches, intraepithelial spaces, and lamina propria and were stained with specific antibodies for B and T cells and for T-cell expression of CD4 and CD8 by flow cytometric analysis. Data were analyzed by analysis of variance. RESULTS: Bombesin prevented the IV TPN decreases in (1) total cell yield and B-cell yield from the Peyer's patches, intraepithelial spaces, and lamina propria; (2) T-cell yield in the intraepithelial spaces and lamina propria; and (3) small intestinal IgA levels. Bombesin also reversed IV TPN decreases in CD4+ and CD8+ T cells in the intraepithelial spaces and Peyer's patches and prevented the decrease in the CD4/CD8 ratio in the lamina propria. CONCLUSION: Bombesin prevents the TPN-associated atrophy and dysfunction of gut-associated lymphoid tissue, supporting the concept of close neuroimmunologic interaction.

Effect of recombinant human insulin-like growth factor I and early total parenteral nutrition on immune depression following severe head injury.

OBJECTIVE: To determine the effects of insulin-like growth factor I (IGF-I) and aggressive nutrition on CD4/CD8 ratios following head injury. DESIGN: Randomized controlled trial. SETTING: An urban level 1 trauma center. PARTICIPANTS: Head-injured patients with a Glasgow Coma Scale score of 4 to 10 within 6 hours of hospital admission requiring no major extracranial surgery with the exception of isolated lower-extremity fracture fixation. Fourteen patients were recruited and 11 completed the study. INTERVENTIONS: Patients were randomized to a continuous infusion of saline or 0.01 mg/kg per hour of recombinant human (rh) IGF-I. Both groups received parenteral nutrition and rapidly advanced to a total protein intake of 2 g/kg per day and a maximum nonprotein calorie intake of 40 kcal/kg per day. The nonprotein prescription was 1.25 times the metabolic energy expenditure determined by metabolic cart not to exceed a nonprotein calorie intake of 40/kcal. MAIN OUTCOME MEASURES: The CD4/CD8 ratios and serum IGF-I levels on days 1, 7, and 14. RESULTS: Administration of early aggressive nutrition eliminated the depressed CD4/CD8 ratio usually seen after head injury; administration of IGF-I increased the CD4/CD8 ratio while IGF-I levels were elevated. CONCLUSIONS: Infusion of rhIGF-I and aggressive early intravenous nutrition affects the immunologic response of patients with severe head injury.

Increased expression of intestinal P-selectin and pulmonary E-selectin during intravenous total parenteral nutrition.

HYPOTHESIS: Intravenous total parenteral nutrition (TPN) induces intestinal polymorphonuclear neutrophil recruitment with increased intestinal intercellular adhesion molecule-1 expression. While intercellular adhesion molecule-1 causes firm adhesion of leukocytes to the endothelial cells, P- and E-selectin mediate leukocyte recruitment via rolling. Therefore, manipulation of nutrition may also affect P- and E-selectin expression in organs. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. MATERIALS: Male mice. INTERVENTIONS: Fifty-three mice were randomized to chow, intravenous TPN, or intragastric TPN. MAIN OUTCOME MEASURES: After 5 days of diet, mice were administered iodine 125-labeled anti-P-selectin antibody (or iodine 125-labeled anti-E-selectin antibody) and iodine 131-labeled nonbinding antibody to quantify P-selectin (or E-selectin) expression in organs (lung, liver, kidney, small intestine, colon, stomach, pancreas, mesentery, heart, and skeletal muscle). RESULTS: P-selectin in small intestine, colon, stomach, and pancreas in the intravenous TPN group increased significantly as compared with the chow and the intragastric TPN groups. E-selectin expression was up-regulated after intravenous TPN in the lung but not in other sites. CONCLUSIONS: In a time frame (5 days) when intercellular adhesion molecule-1 expression and neutrophil recruitment are increased, intestinal expression of P-selectin remains up-regulated. Early lung inflammatory changes are reflected by increases in E-selectin. This change may reflect early pulmonary dysfunction with intravenous TPN, but its significance requires further study.

Pneumonia and stress ulceration in severely injured patients. A prospective evaluation of the effects of stress ulcer prophylaxis.

Stress ulcer prophylaxis is a routine aspect of the care of critically injured patients. Recent reports have suggested that patients undergoing prophylaxis with histamine antagonists are predisposed to nosocomial pneumonia, and that treatment with sucralfate can prevent this problem. An open, prospective randomized trial of three regimens was conducted with 278 evaluable patients. The patients were assigned to one of three group: the group receiving sucralfate, the group receiving a cimetidine hydrochloride bolus, and the group undergoing continuous infusion with cimetidine. Stress ulceration developed in 8% of patients in the sucralfate group, 13% of patients in the cimetidine bolus group, and 12% of patients in the cimetidine infusion group, while nosocomial pneumonia developed in 29% of patients in the sucralfate group, 32% of patients in the cimetidine bolus group, and 23% of patients in the cimetidine infusion group. Multivariate analysis of risk factors associated with pneumonia demonstrated independent significance for score on the Glasgow Coma Scale, Injury Severity Score, cord injury, shock, and head injury. Only spinal cord injury was associated with stress ulceration. We conclude that sucralfate and cimetidine are both effective for stress ulcer prophylaxis and that there is no association of cimetidine with nosocomial pneumonia.