Christopher F. Brandt

Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1 + GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study

BACKGROUND AND AIMS The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake, this study evaluated the acute effects of continuous intravenous administration of glucagon-like peptide (GLP) 1 and 2, alone or in combination, on gastrointestinal function in SBS patients. METHODS SBS patients were admitted 4 times for identical 72-h balance studies, where infusions (1 pmol/kg/min) of GLP-1, placebo (saline), GLP-2 and GLP-1+2 (1 pmol/kg/min of each), were provided. Patients filled out a VAS questionnaire regarding subjective symptoms during treatments. Bone mineral content, body-weight and -composition were measured using DEXA scans. Blood glucose, insulin, pro insulin C-peptide and GLP concentrations were measured in relation to a standardized breakfast. RESULTS Nine SBS patients (5 women/4 men, aged 52±11) were enrolled and completed the study; 7 had end-jejunostomies, 2 had 50% of colon-in-continuity. All treatments significantly reduced the fecal wet weight, energy, nitrogen, sodium and potassium losses compared to placebo. However, only GLP-2 containing treatments increased absolute absorption of wet weight and sodium. Only GLP-1+2 improved the hydrational status evaluated by DEXA increases in the fat mass and calculated total body weight. GLP-1 and GLP-1+2 reduced the post-prandial blood glucose levels. A tendency of nausea and reduced appetite was seen in relation to GLP-1 treatment, but this was ameliorated by the co-administration of GLP-2. CONCLUSION GLP-1 decreased diarrhea and fecal excretions in SBS patients, but it seems less potent than GLP-2. The combination of GLP-1+2 numerically provided additive effects on intestinal absorption compared to either peptide given alone. Larger, long-term studies should further assess the potential of the glucagon-like peptides or analogs, alone or in combination, in the treatment of SBS patients.

Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients.

BACKGROUND In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunostomy short bowel syndrome (SBS) patients. METHODS In five SBS patients with end-jejunostomy a specially designed laser Doppler probe was inserted into the stoma nipple, and blood flow measured directly on the jejunal mucosa for 105 min in relation to no treatment, systemic saline infusion, topical adrenaline application and a subcutaneous injection of 800 μg native GLP-2. RESULTS The GLP-2 injection increased jejunal mucosal blood flow by 79±37% compared to conditions, where no treatment was given (p<0.001). The significant effect was present at least 105 min. Systemic saline infusion and topical, mucosal adrenaline application did not affect mucosal microcirculation. CONCLUSIONS GLP-2 raises jejunal microcirculation in SBS patients with end-jejunostomy. This may explain the redness and increase in the end-jejunostomy nipple size imminently after commencing GLP-2 injections. The potential beneficial effects of this GLP-2-mediated increase of blood flow in the mesenteric bed should be investigated in clinical conditions other than the short bowel syndrome.

Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure The Evolution Over 4 Decades in a Tertiary Referral Center

Background/Aims: In Denmark, the public healthcare system ensures patients with intestinal failure (IF) the same rights for a life-saving treatment as patients with other organ failures. This study reports the epidemiological data from the largest Danish IF center. As one of the pioneering centers in treating IF with home parenteral nutrition (HPN), this study documents the HPN evolution and describes the demographics and outcome in one of the world’s largest single-center cohorts. Methods: We included patients with IF discharged with HPN from 1970–2010. Data were extracted according to European Society for Clinical Nutrition and Metabolism classifications from the Copenhagen IF database. Results: Over the decades, we observed an exponential increase in the number of HPN patients. The 508 patients with IF collectively received HPN for 1751 years. While receiving HPN, 211 patients with IF (42%) died. Only 24 deaths were HPN related: sepsis (n = 10), liver disease (n = 12), central venous thrombosis (n = 1), and a complicated catheter placement (n = 1). The HPN-related mortality was as low as 0.014 deaths/HPN year. In the first decade, HPN was mainly provided to younger, intestinally resected adult patients with IF with inflammatory bowel disease (IBD), but numerically, they were subsequently outnumbered by elderly patients with IF with cancer or complications from non-IBD, noncancer abdominal surgery. Despite these demographic changes, the HPN-related mortality has decreased in the past decade. Conclusion: Evolving from being a rare, experimental treatment in the 1970s, HPN at present is safe with a low treatment-related mortality in the experienced center, despite HPN being more widely used in a more elderly population.

Home Parenteral Nutrition in Adult Patients With Chronic Intestinal Failure: Catheter-Related Complications Over 4 Decades at the Main Danish Tertiary Referral Center

BACKGROUND/AIMS Catheter-related complications (CRCs) cause mortality and morbidity in patients dependent on parenteral support at home (HPN) due to intestinal failure (IF). This study describes the incidences of CRCs in an adult IF cohort over 40 years. It illustrates the evolution and consequences of CRCs, their association to demographic characteristics, and potential risk factors in an effort to provide the rationale for preventive precautions to the relevant patients with IF at risk. METHODS All patients with IF discharged with HPN from 1970-2010 were included. Patient and treatment characteristics were extracted from the Copenhagen IF database. The incidences were given per 1000 central venous catheter (CVC) days. RESULTS The 1715 CRCs occurred in 70% of the 508 patients with IF (56% of the 2191 CVCs). The incidence of catheter-related bloodstream infections (CRBSIs) was 1.43. Higher age, HPN administration by community home nurses, and prior CRBSIs significantly raised the hazard for CRBSIs. In the 1970s, catheters were generally replaced following CRBSIs, whereas catheter salvage was the norm in the 2000s. The incidences of mechanical complications, tunnel infections, and catheter-related venous thromboses were 0.80, 0.25, and 0.11, respectively. The overall CRC incidence was 2.58, decreasing the first 3 decades but peaking in the last (2.84). The deaths related to CRCs were low (0.018). CONCLUSION Even in an experienced IF center of excellence, the incidence of CRCs increased over the 4 decades. This increase could be explained by the expansion of the indication of HPN to a more elderly and frail patient population.

Taurolidine-citrate-heparin lock reduces catheter-related bloodstream infections in intestinal failure patients dependent on home parenteral support: a randomized, placebo-controlled trial

Background: In patients with intestinal failure who are receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) inflict health impairment and high costs.Objective: This study investigates the efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared with heparin 100 IE/mL on CRBSI occurrence.Design: Forty-one high-risk patients receiving HPS followed in a tertiary HPS unit were randomly assigned in a double-blinded, placebo-controlled trial. External, stratified randomization was performed according to age, sex, and prior CRBSI incidence. The prior CRBSI incidence in the study population was 2.4 episodes/1000 central venous catheter (CVC) days [95% Poisson confidence limits (CLs): 2.12, 2.71 episodes/1000 CVC days]. The maximum treatment period was 2 y or until occurrence of a CRBSI or right-censoring because of CVC removal. The exact permutation tests were used to calculate P values for the log-rank tests.Results: Twenty patients received the taurolidine-citrate-heparin lock and 21 received the heparin lock, with 9622 and 6956 treatment days, respectively. In the taurolidine-citrate-heparin arm, no CRBSIs occurred, whereas 7 CRBSIs occurred in the heparin arm, with an incidence of 1.0/1000 CVC days (95% Poisson CLs: 0.4, 2.07/1000 CVC days; P = 0.005). The CVC removal rates were 0.52/1000 CVC days (95% Poisson CLs: 0.17, 1.21/1000 CVC days) and 1.72/1000 CVC days (95% Poisson CLs: 0.89, 3.0/1000 CVC days) in the taurolidine-citrate-heparin and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm (P = 0.06). Costs per treatment year were lower in the taurolidine arm (€2348) than in the heparin arm (€6744) owing to fewer admission days related to treating CVC-related complications (P = 0.02).Conclusions: In patients with intestinal failure who are life dependent on HPS, the taurolidine-citrate-heparin catheter lock demonstrates a clinically substantial and cost-beneficial reduction of CRBSI occurrence in a high-risk population compared with heparin. This trial was registered at clinicaltrials.gov as NCT01948245.

A Single-Center, Adult Chronic Intestinal Failure Cohort Analyzed According to the ESPEN-Endorsed Recommendations, Definitions, and Classifications.

Background/Aims: The objective of this study was to describe a clinically well-defined, single-center, intestinal failure (IF) cohort based on a template of definitions and classifications endorsed by the European Society for Clinical Nutrition and Metabolism (ESPEN). Methods: A cross-sectional, retrospective, adult IF cohort, receiving parenteral support (PS), was extracted from the Copenhagen IF database at the tertiary IF center, Copenhagen University Hospital, Rigshospitalet, Denmark. Results: Rigshospitalet provided PS to 188 adult patients with IF on December 31, 2011. Six patients received only fluids and electrolytes, while 97% required parenteral energy (17 ± 12 kcal/kg/d). Although 92% of the cohort had undergone intestinal resection, only 53% were classified as patients with short bowel syndrome (SBS) according to the pathophysiological classification. In the remaining cohort, patients were distributed as 5% with intestinal fistula, 12% with intestinal dysmotility, 5% with mechanical obstruction, and 14% with mucosal diseases. Twelve percent had a combination of pathophysiological causes. The patients with SBS (n = 100) were subdivided according to bowel anatomy into group 1 (jejuno/ileostomy, n = 82), group 2 (jejuno-colonic-anastomosis, n = 16), and group 3 (jejuno-ileo-colonic-anastomosis, n = 2). When evaluating the cohort requirements for PS using the ESPEN chronic IF classification based on the need for fluid volume and energy, 53% of the patients with IF were distributed in the maximum categories. Conclusion: The orphan condition of IF with its large patient heterogeneity mandates establishment of uniform definitions and a harmonization of classifications. As illustrated, the ESPEN-endorsed definitions and classifications are well designed and may serve as a common uniform template to facilitate both intra- and intercenter comparisons between reference centers and thus outcome results.

A dose-equivalent comparison of the effects of continuous subcutaneous glucagon-like peptide 2 (GLP-2) infusions versus meal related GLP-2 injections in the treatment of short bowel syndrome (SBS) patients.

OBJECTIVE Glucagon-like peptide 2 (GLP-2), secreted endogenously from L-cells in the distal bowel in relation to meals, modulates intestinal absorption by adjusting gastric emptying and secretion and intestinal growth. Short bowel syndrome (SBS) patients with distal intestinal resections have attenuated endogenous GLP-2 secretion, which may contribute to their rapid gastric emptying, gastric hypersecretion and poor intestinal adaptation, whereas SBS patients with preserved terminal ileum and colon, who have a constantly elevated GLP-2 secretion, seem to do better in these respects. This study compared effects of continuous, subcutaneous (s.c.), exogenous GLP-2 infusion (CONT-GLP-2) versus three daily s.c. GLP-2 injections (TID-GLP-2) on intestinal absorption in SBS patients. DESIGN Eight SBS patients (5 F, 3 M; 60±7 years; remnant small bowel 111±62 cm; 1 with 50% colon) were studied. In an open-label, sequential study, the 72-hour baseline admission was followed by two dose-equivalent, 21-day, dosing regimens; CONT-GLP-2, providing 1.0mg/day by a MiniMed insulin pump and TID-GLP-2, providing 0.33 mg injections in relation to three meals, separated by a washout period of at least 3 weeks. During admissions, the intestinal absorption was evaluated by analysing a double portion of the diet, faecal and urinary excretions. Post-absorptive plasma citrulline, reflecting enterocyte mass, was measured by HPLC. RESULTS Compared to baseline, both GLP-2 dosing regimens reduced diarrhoea (CONT-GLP-2: 749±815 g/d and TID-GLP-2: 877±1004 g/d, p=0.01) and increased wet weight absorption (CONT-GLP-2: 19±19% and TID-GLP-2: 25±21%, p=0.003). Significant increases in plasma citrulline (CONT-GLP-2: 7.5±7 μmol/L and TID-GLP-2, 12.7±8 μmol/L; p=0.001) suggesting intestinotrophic effects in relation to GLP-2 treatment, are followed by increases in relative absorption of energy, carbohydrate and fat. No significant difference was seen on any of the absorptive parameters measured between the two dosing regimens. CONCLUSION Both GLP-2 regimens significantly reduced diarrhoea in SBS patients, but a significant difference between continuous GLP-2 administration and TID injections could not be detected in a study of this size.

The use of metabolic balance studies in the objective discrimination between intestinal insufficiency and intestinal failure

Background: In research settings that use metabolic balance studies (MBSs) of stable adult patients with short bowel syndrome, intestinal failure (IF) and dependence on parenteral support (PS) have been defined objectively as energy absorption <84% of calculated basal metabolic rate (BMR), wet weight (WW) absorption <23 g · kg body weight-1 · d-1, or both. Objective: This study aimed to explore and validate these borderlines in the clinical setting.Design: Intestinal absorption was measured from April 2003 to March 2015 in 175 consecutive patients with intestinal insufficiency (INS) in 96-h MBSs. They had not received PS 3 mo before referral.Results: To avoid the need for PS, the minimum absorptive requirements were energy absorption of ≥81% of BMR and WW absorption of ≥21 g · kg body weight-1 · d-1, which were equivalent to findings in research settings (differences of 3.6% and 8.7%; P = 0.65 and 0.60, respectively). Oral failure defined as energy intake <130% of calculated BMR or WW intake <40 g · kg body weight-1 · d-1 was seen in 71% and 82% of the 10% of patients with the lowest energy absorption and WW absorption, respectively.Conclusions: In clinical settings, the borderlines between INS and IF were not significantly different from those in research settings, even in an unselected patient population in which oral failure was also a predominant cause of nutritional dyshomeostasis. MBSs may be recommended to identify the individual patient in the spectrum from INS to IF, to objectivize the cause of nutritional dyshomeostasis (oral failure, malabsorption, or both), and to quantify the effects of treatment.

Su2095 Survival and Cause-Specific Mortality in an Intestinal Failure Cohort Depending on Home Parenteral Nutrition (HPN) in a Referral Centre From 1970 to 2010

G A A b st ra ct s enhanced microbial fermentation of dietary fiber and dysregulation of choline metabolism. The OPLS-DA model constructed based on samples collected post DI (R2X=30.7%, Q2Y= 0.37) showed higher concentrations of glutamate and 6-aminosalicylic acid in AA compared with AF. Microbial data acquired using HITChip was integrated with fecal profiles using OPLS. At the phylum level, 2 out of 22 identified phyla were significantly correlated with fecal profiles, which are Cyanobacteria and uncultured Mollicutes significantly correlating with fecal glutamate and valerate. By statistically integrating the fecal metabonome and the 130 microbial genus, Bacteroides vulgates et rel. and Bacteroides plebeius et rel. were observed to be correlated with choline, whereas Uncultured Clostridiales II was correlated with pyroglutamate. Uncultured Mollicutes, Eubacterium siraeum et rel and Aneurinibacillus demonstrated similar metabolic activity. Conclusions: These findings indicate that after only two-weeks of a dietary exchange diet, the fecal metabolic profile is significantly altered and that these metabolic changes are closely associated with alterations in the structure and function of the gut microbial network.

577 A Potential Association Between Remnant Bowel Anatomy and the Incidence of Catheter-Related Blood-Stream Infections (CRBSIS) in Adult Intestinal Failure (IF) Patients Depending in Home Parenteral Nutrition(HPN)

Patients with intestinal failure (IF) depend on parenteral support through a central line for survival, but are challenged by the risk of catheter-related bloodstream infections (CRBSIs). Employing the Copenhagen HPN database, we investigated the association between the remaining bowel anatomy and the incidence and infectious species in CRBSIs with the aim of identifying risk factors. Methods: The CopenhagenHPNdatabase is based on a retrospective annually review of all charts from adult patients, who have received HPN from Rigshospitalet, Denmark. The diagnosis of a CRBSI required clinical signs of a systemic infection and positive blood cultures, with the exclusion of other causes of infections. Results: From 1970 to 2010, 510 IF patients were discharged with HPN, in total contributing to 1745 HPN years. In 256 of the IF patients 873 CRBSI were detected: 595 mono-bacteraemia, 140 polybacteraemia, 85 fungemia and 49 combinations of bacteraemia and Candidemia. The species of bacteraemia and Candidemia were determined in 869 CRBSIs, while 4 positive cultures were recorded without species. The cohort were divided into three groups according to remain bowel anatomy (-colon, +colon and no-surgical). The overall incidence of CRBSIs in HPN were 1.37 per 1000 HPN days. In the group without colon, the incidence of CRBSIs were 1.54 per 1000 HPN days. The median remaining small intestine was 125 cm, and the median age at complication was 57.8 years. The group were subdivided dependent on the remaining small intestine ( 200cm) with minor variations in incidence (1.59, 1.69, 1.42 and 1.60 per 1000 HPN days). The CRBSI incidence in IF patients with remaining colon was 0.92 per 1000 HPN days. The median small intestine was 100 cm, and the patients had a median of 70.5% of remaining colon. The median age at complication in this group was 49.1 years. The colon-group was first split into two: less/ above 50% remaining colon with CBRSI incidences of 0.42 and 1.06 per 1000 HPN days. Staphylococcus spp were detected in 55 % of blood cultures in IF patients with colon, while only seen in 30 % in IF patients without remaining colon. In the no colon group enterobacteriaceae were more frequent (50 %) with the exception of IF patients with < 50 cm small intestine (24 %). Candidemia were detected in 14 % of the cultures from IF patients without colon, while only 6.8 % in IF patients with colon. Conclusion: The CRBSI incidence rate in IF patients without colon is almost two fold higher compared to IF patients with remaining colon. Most frequently IF patients with a colon had bacteraemia with Staphylococci, while CRBSI in patients without a colon as frequently were caused by enterobacteriaceae. Candidemia was most frequently seen in patients without colon. The role of remaining bowel on the incidence of CRBSI needs further investigation. Tabel 1: Incidence of CRBSIs in HPN years and 1000 HPN days.