Protein-based oral rehydration solutions for patients with an ileostomy: A randomised, double-blinded crossover study.

BACKGROUND & AIM: Patients with an ileostomy are at increased risk of dehydration and sodium depletion. Treatments recommended may include oral rehydration solutions (ORS). We aimed to investigate if protein type or protein hydrolysation affects absorption from iso-osmolar ORS in patients with an ileostomy. METHODS: This was a randomised, double-blinded, active comparator-controlled 3 × 3 crossover intervention study. We developed three protein-based ORS with whey protein isolate, caseinate or whey protein hydrolysate. The solutions contained 40-48 g protein/L, 34-45 mmol sodium/L and had an osmolality of 248-270 mOsm/kg. The patients ingested 500 mL/d. The study consisted of three 4-week periods with a >2-week washout between each intervention. The primary outcome was wet-weight ileostomy output. Ileostomy output and urine were collected for a 24-h period before and after each intervention. Additionally, blood sampling, dietary records, muscle-strength tests, bioimpedance analyses, questionnaires and psychometric tests were conducted. RESULTS: We included 14 patients, of whom 13 completed at least one intervention. Ten patients completed all three interventions. Wet-weight ileostomy output did not change following either of the three interventions and did not differ between interventions (p = 0.38). A cluster of statistically significant improvements related to absorption was observed following the intake of whey protein isolate ORS, including decreased faecal losses of energy (-365 kJ/d, 95% confidence interval (CI), -643 to -87, p = 0.012), potassium (-7.8 mmol/L, 95%CI, -12.0 to -3.6, p = 0.001), magnesium (-4.0 mmol/L, 95%CI, -7.4 to -0.7, p = 0.020), improved plasma aldosterone (-4674 pmol/L 95%CI, -8536 to -812, p = 0.019), estimated glomerular filtration rate (eGFR) (2.8 mL/min/1.73 m2, 95%CI, 0.3 to 5.4, p = 0.03) and CO2 (1.7 mmol/L 95%CI, 0.1 to 3.3, p = 0.04). CONCLUSION: Ingestion of 500 mL/d of iso-osmolar solutions containing either whey protein isolate, caseinate or whey protein hydrolysate for four weeks resulted in unchanged and comparable ileostomy outputs in patients with an ileostomy. Following whey protein isolate ORS, we observed discrete improvements in a series of absorption proxies in both faeces and blood, indicating increased absorption. The protein-based ORS were safe and well-tolerated. Treatments should be tailored to each patient, and future studies are warranted to explore treatment-effect heterogeneity and whether different compositions or doses of ORS can improve absorption and nutritional status in patients with an ileostomy. GOV STUDY IDENTIFIER: NCT04141826.

Post-prandial secretion of glucagon-like peptide-2 (GLP-2) after carbohydrate-, fat- or protein enriched meals in healthy subjects.

Glucagon-like peptide 2 (GLP-2) is an important regulator of intestinal growth and function. In adherable mixed meals the macronutrient composition with the best potential for stimulating GLP-2 secretion is not known. We compared the effect of 3 iso-energetic meals, where approximately 60 % of the energy ratio was provided as either carbohydrate, fat, or protein, respectively, on the post-prandial endogenous GLP-2 secretion. The responses were compared to secretion profiles of peptide YY (PYY), and glucose-dependent insulinotropic peptide (GIP). Ten healthy subjects were admitted on three occasions, at least a week apart, after a night of fasting. In an open-label, crossover design, they were randomized to receive a high carbohydrate (HC), high fat (HF) or high protein (HP) meal. The meals were approximately ∼3.9 MJ. Venous blood was collected for 240 min, and plasma concentrations of GLP-2, GIP and PYY were measured with specific radioimmunoassays. Mean GLP-2 levels peaked already at 30 min for the HC meal, however the HP meal induced the highest mean GLP-2 peaking levels, resulting in significantly higher mean GLP-2 area under the curve (AUC) from baseline of 7279 pmol*min/L, 95 %-CI [6081;8477] compared to the HC meal: 4764 pmol*min/L, 95 %-CI [3498;6029], p = 0.020 and the HF meal: 4796 pmol*min/L, [3385;6207], p = 0.011. Findings were similar for the PYY. The HC meal provided a greater AUC for GIP compared to the HP- and HF meals. The HP meal was most effective with respect to stimulation of the postprandial GLP-2 and PYY secretion, whereas the HC meal was more effective for GIP.

Effects of glepaglutide, a long-acting glucagon-like peptide-2 analog, on intestinal morphology and perfusion in patients with short bowel syndrome: Findings from a randomized phase 2 trial.

BACKGROUND: The proadaptive effects of glucagon-like peptide-2 (GLP-2) include stimulation of intestinal mucosal growth as well as intestinal blood flow and angiogenesis. We have recently reported that daily subcutaneous injections of glepaglutide, a long-acting GLP-2 analog, improved intestinal absorptive function in patients with short bowel syndrome (SBS). As secondary and exploratory end points, the effects of glepaglutide on intestinal morphology and perfusion are reported. METHODS: The following assessments were done in 18 patients with SBS in a randomized, crossover, dose-finding, phase 2 trial before and after three weeks of treatment with glepaglutide: plasma citrulline and mucosa biopsies to assess changes in (1) intestinal morphology by immunohistochemistry and (2) gene expressions associated with absorption, proliferation, and markers of tight-junction integrity by quantitative polymerase chain reaction. Intestinal perfusion was assessed in stoma nipples by laser speckle contrast imaging and quantitative fluorescence angiography with indocyanine green. RESULTS: In the 1- and 10-mg dose groups, glepaglutide significantly increased plasma citrulline by 15.3 µmol/L (P = 0.001) and 15.6 µmol/L (P = 0.001), respectively. Trends toward an increase in villus height, crypt depth, and epithelium height were seen in the same groups. No significant changes were seen in gene expressions or intestinal perfusion. CONCLUSION: The increase in plasma citrulline and the morphological improvements may partly account for improvement in the intestinal absorptive function. However, the finding of a stability in perfusion after three weeks of treatment with glepaglutide may have been preceded by a more profound acute-phase increase in intestinal perfusion at treatment initiation.

Apraglutide, a novel once-weekly glucagon-like peptide-2 analog, improves intestinal fluid and energy absorption in patients with short bowel syndrome: An open-label phase 1 and 2 metabolic balance trial.

BACKGROUND: Apraglutide is a novel long-acting glucagon-like peptide-2 (GLP-2) analog designed for once-weekly subcutaneous dosing, with the potential to increase fluid and nutrient absorption by the remnant intestine of patients who have short bowel syndrome (SBS) with intestinal insufficiency (SBS-II) or intestinal failure (SBS-IF). This trial investigated the safety and effects on intestinal absorption of apraglutide in patients with SBS-II and SBS-IF. METHODS: In this open-label, phase 1 and 2 trial, adult patients with SBS-II (n = 4) or SBS-IF (n = 4) and a fecal output of ≥1500 g/day received once-weekly subcutaneous 5 mg apraglutide for 4 weeks. Safety was the primary end point. Secondary end points included change from baseline in intestinal absorption of wet weight (indicative of fluid absorption), electrolytes, and energy (by bomb calorimetry) measured by inpatient metabolic balance studies. RESULTS: Common treatment-related adverse events were decreased gastrointestinal (GI) stoma output (n = 6), stoma complications (n = 6), GI stoma complications (n = 5), nausea (n = 5), flatulence (n = 4), abnormal GI stoma output (n = 4), polyuria (n = 3), and abdominal pain (n = 3). The only treatment-related serious adverse event (experienced in one patient) was abdominal pain. Apraglutide significantly increased wet weight and energy absorption by an adjusted mean of 741 g/day (95% CI, 194 to 1287; P = 0.015) and 1095 kJ/day (95% CI, 196 to 1994; P = 0.024), respectively. Sodium and potassium absorption significantly increased by an adjusted mean of 38 mmol/day (95% CI, 3 to 74; P = 0.039) and 18 mmol/day (95% CI, 4 to 32; P = 0.020), respectively. CONCLUSION: Once-weekly 5 mg apraglutide was well tolerated in patients with SBS-II and SBS-IF and significantly improved the absorption of fluids, electrolytes, and energy.

Apraglutide, a novel glucagon-like peptide-2 analog, improves fluid absorption in patients with short bowel syndrome intestinal failure: Findings from a placebo-controlled, randomized phase 2 trial.

BACKGROUND: Treatment with glucagon-like peptide-2 (GLP-2) analogs improve intestinal adaptation in patients with short bowel syndrome-associated intestinal failure (SBS-IF) and may reduce parenteral support requirements. Apraglutide is a novel, long-acting GLP-2 analog designed for once-weekly dosing. This trial investigated the safety and efficacy of apraglutide in patients with SBS-IF. METHODS: In this placebo-controlled, double-blind, randomized, crossover phase 2 trial, eight adults with SBS-IF were treated with once-weekly 5-mg apraglutide doses and placebo for 4 weeks, followed by once-weekly 10-mg apraglutide doses for 4 weeks, with a washout period of 6-10 weeks between treatments. Safety was the primary end point. Secondary end points included changes from baseline in urine volume output compared with placebo, collected for 48 h before and after each treatment period. RESULTS: Common treatment-related adverse events (AEs) were mild to moderate and included polyuria, decreased stoma output, stoma complications, decreased thirst, and edema. No serious AEs were considered to be related to apraglutide treatment. The safety profile was comparable for the lower and higher doses. Treatment with once-weekly 5- and 10-mg apraglutide doses significantly increased urine volume output by an adjusted mean of 714 ml/day (95% CI, 490-939; P < .05) and 795 ml/day (95% CI, 195-1394; P < .05), respectively, compared with placebo, with no significant differences between doses. CONCLUSIONS: Once-weekly apraglutide was well tolerated at both tested doses and significantly increased urine volume output, providing evidence for increased intestinal fluid absorption. A phase 3 trial is underway in adults with SBS-IF.

Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial.

BACKGROUND: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS). METHOD: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry. RESULTS: Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (-169, -28; p = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. CONCLUSION: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study.

OBJECTIVE: Patients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group. DESIGN: In an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment. RESULTS: Of the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (-174 g/day (-1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day. CONCLUSION: Following this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.

Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial.

BACKGROUND: Patients with short bowel syndrome (SBS) and distal-bowel resections lack neuroendocrine feedback regulations, potentially resulting in rapid gastrointestinal (GI) transit. The objective was to assess the efficacy of glepaglutide, a long-acting glucagon-like peptide-2 analog, on GI transit in patients with SBS. METHODS: In this single-center, double-blind, dose-finding, phase 2 trial, patients with SBS were randomly assigned to 3 treatments (0.1, 1, and 10 mg) in a 2-period crossover design. Each treatment period included 3 weeks of daily, subcutaneous glepaglutide injections separated by a washout period of 4-8 weeks. Endpoints were changes from baseline and included scintigraphy, wireless motility capsule (WMC, SmartPill Given Imaging, Ltd, Yokneam, Israel), and paracetamol absorption test. RESULTS: A total of 18 patients were randomized. In the 10-mg dose group (n = 9), glepaglutide significantly increased time to 10% gastric emptying (GE) of solids by 27 (4-50) minutes (adjusted mean [95% CI]), time to 50%GE of fluids by 40 (1-80) minutes, and time to 10% small bowel-emptying of solids by 21 (1-41) minutes. The WMC transit did not significantly change in any of the dose groups. The maximum paracetamol concentration significantly increased in the 10-mg dose group; however, the area under the curve remained the same. CONCLUSION: The prolonged GI transit after glepaglutide treatment, along with demonstrated positive effects on intestinal mucosal growth and potential effects on GI hypersecretions, is believed to contribute to the observed beneficial effects on fecal output (primary endpoint) and associated improvement in intestinal absorption.

Repeated Metabolic Balance Studies in Patients With Short Bowel Syndrome.

BACKGROUND: Weaning from parenteral support is considered indirect evidence of intestinal adaptation in patients with short bowel syndrome (SBS), but direct evidence is lacking. The objective of this study was to examine if intestinal adaptation could be demonstrated as increase in intestinal absorption of energy and wet weight over time measured by repeated metabolic balance studies (MBSs) and to examine whether adaptation was determined by the anatomy of the remnant bowel. METHODS: We retrospectively analyzed data from 48 repeated MBSs performed in 13 adult patients with SBS. Results were presented graphically and interpreted. The interpatient and intrapatient heterogeneity was compared based on anatomy of the remnant bowel. RESULTS: The number of repeated MBSs ranged from 2 to 7, and time between last intestinal resection and MBS from 5 months to 18.1 years. In 6 patients, the first MBS was performed within 2 years after last resection, but only 1 patient had repeated MBSs within this period. Nine patients had an end jejunoileostomy, and 4 patients had a jejuno-colonic or ileo-colonic anastomosis. None of the patients had jejunoileal anastomosis with a preserved ileocecal valve. Interpatient and intrapatient heterogeneity of wet weight and energy absorption was larger in patients without colon in continuity. The wet weight and energy absorption data showed no tendency toward intestinal adaptation in any anatomical group. CONCLUSION: We observed no signs of late-phase intestinal adaptation in this selected group of patients with SBS. Future prospective MBSs are needed to understand the time course and magnitude of intestinal adaptation.

Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial.

BACKGROUND: With the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage. We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function. METHODS: Liver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025. FINDINGS: Between Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected. INTERPRETATION: Glepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies. FUNDING: Zealand Pharma.

Glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, for patients with short bowel syndrome: a randomised phase 2 trial.

BACKGROUND: Patients with short bowel syndrome might have impaired postprandial endogenous glucagon-like peptide-2 (GLP-2) secretion, which is required for optimal intestinal adaptation. We aimed to assess the therapeutic potential of glepaglutide, a novel long-acting GLP-2 analogue, for reducing faecal output and increasing intestinal absorption in patients with short bowel syndrome. METHODS: In this single-centre, double-blind, crossover, randomised phase 2 trial, adults (aged ≥18 to ≤90 years) with short bowel syndrome and with a faecal wet weight output of 1500 g/day or more were randomly assigned to receive one of six dose sequences of glepaglutide (10 mg, 1 mg; 10 mg, 0·1 mg; 1 mg, 10 mg; 1 mg, 0·1 mg; 0·1 mg, 10 mg; or 0·1 mg, 1 mg). Patients received daily subcutaneous injections of the first assigned dose of glepaglutide for 3 weeks, followed by a washout period of 4-8 weeks, and then the second dose of glepaglutide for 3 weeks. An unmasked statistician generated the randomisation list, and the trial investigator enrolled patients and assigned them their patient numbers. Trial investigators, patients, and other care providers were masked throughout the trial. The primary endpoint was the absolute change from baseline in faecal wet weight output, measured separately over the two treatment periods. Metabolic balance studies were done before and after each treatment period to assess the primary endpoint. Per-protocol analysis was used to assess the efficacy. Safety analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02690025, and has completed. FINDINGS: Of the 22 patients screened between Feb 5, 2016, and Jan 25, 2017, 18 patients were randomly assigned and treated with glepaglutide; 16 patients completed the trial. Treatment with 1 mg and 10 mg glepaglutide changed the adjusted mean faecal output by -592 g/day (95% CI -913 to -272; p=0·002) and -833 g/day (-1152 to -515; p=0·0002) from baseline, respectively. No changes were observed with 0·1 mg glepaglutide. Of the 18 patients who were randomly assigned to treatment, common treatment-related adverse events were stoma complications (13 [72%] patients), injection site reactions (11 [61%]), peripheral oedema (ten [56%]), nausea and abdominal pain (eight [44%] each), polyuria and fatigue (six [33%] each), abdominal distention, vomiting, and dizziness (five [28%] each); and cough and decreased appetite (four [22%] each). Related or possibly related serious adverse events were reported in two patients in the 0·1 mg dose group and two patients in the 10 mg dose group. These events included abdominal pain, stoma obstruction, catheter-related sepsis, and infection of unknown origin. No patients died during the trial. INTERPRETATION: Glepaglutide was well tolerated, and was associated with improved intestinal absorption in patients with short bowel syndrome with 1 mg and 10 mg glepaglutide, but not with 0·1 mg glepaglutide. Larger phase 3 clinical trials of longer durations have been initiated to fully assess the safety and efficacy of glepaglutide. FUNDING: Zealand Pharma.

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.

Catheter-Related Bloodstream Infections in Adults Receiving Home Parenteral Nutrition: Substantial Differences in Incidence Comparing a Strict Microbiological to a Clinically Based Diagnosis.

BACKGROUND: A common complication in patients receiving home parenteral nutrition (HPN) is catheter-related bloodstream infections (CRBSIs). The CRBSI incidence has been advocated as an outcome parameter assessing the quality of care. This study aimed to illustrate how the use of different CRBSI definitions affects the reported incidence. MATERIALS AND METHODS: In an observational study based on the Copenhagen intestinal failure database, all clinically reported CRBSIs from 2002-2013 were compared with data from the affiliated microbiological database according to recommended CRBSI criteria. RESULTS: Clinically, 1034 CRBSIs were observed in 548 adults receiving HPN for 1410 catheter-years. Thus, the clinically assessed CRBSI incidence was 1.95/1000 catheter-days. However, based on the microbiological evaluation, only 47% of our episodes fulfilled the Centers for Disease Control and Prevention (CDC) and European Society for Clinical Nutrition (ESPEN) CRBSI criteria. Employing a catheter-salvaging strategy, 40% of the CRBSI diagnoses were supported by the paired blood culture positivity criteria and only 6% by a positive catheter tip. In 53%, CRBSIs were categorized as a clinical or "probable CRBSI" diagnosis. In 20% of all episodes, missing information/blood cultures hampered a CDC/ESPEN CRBSI diagnosis. Thereby, according to CDC/ESPEN CRBSI definitions, the incidence was 0.92/1000 days or 46% lower than clinically assessed. CONCLUSION: This study illustrates the practical and methodological challenges and great variability in reporting of the CRBSI incidence. Nonetheless, it is recommended as a marker of the quality of care. Consensus regarding CRBSI definitions is a prerequisite for a meaningful comparison of this important outcome parameter between HPN centers.

Fasting and Postprandial Plasma Citrulline and the Correlation to Intestinal Function Evaluated by 72-Hour Metabolic Balance Studies in Short Bowel Jejunostomy Patients With Intestinal Failure.

BACKGROUND: Fasting plasma citrulline (p-citrulline) is a marker of functional enterocyte mass. However, the optimal timing of measurement in relation to meals has yet to be clarified. Furthermore, p-citrulline has been proposed to be a surrogate marker for small bowel length and intestinal absorption parameters in short bowel syndrome patients with intestinal failure (SBS-IF). MATERIALS AND METHODS: Eight patients with SBS-IF and 8 healthy controls (HCs) were given a standardized mixed test meal, and p-citrulline was measured 15 minutes before and 60, 120, and 180 minutes after completion of the meal. The patients with SBS-IF had their intestinal absorption of wet weight, energy, macronutrients, and electrolytes measured in relation to 72-hour metabolic balance studies. We investigated the possible correlations between p-citrulline and short bowel length, absorptive parameters, and the dependence on parenteral support (PS). RESULTS: In the patients with SBS-IF, we found a 12% (P = .041) reduction in postprandial citrulline levels after 180 minutes. In the HCs, there was a 13% postprandial reduction at 60 minutes (P = .018). No significant correlations between fasting p-citrulline and bowel length, bowel absorptive function, or the dependence on PS were found. Even when excluding 2 patients in whom the intestinal absorption was adjacent to the intestinal insufficiency borderlines, these correlations were not significant. CONCLUSION: Based on findings in this small study, the optimal timing of p-citrulline measurement is on fasting samples. However, p-citrulline seems insufficiently discriminative to serve as a valid biomarker of bowel length, bowel absorptive function, or dependence on PS in patients with SBS-IF.

Effect of Liraglutide Treatment on Jejunostomy Output in Patients With Short Bowel Syndrome: An Open-Label Pilot Study.

BACKGROUND: An impaired hormonal "ileo-colonic brake" may contribute to rapid gastric emptying, gastric hypersecretion, high ostomy losses, and the need for parenteral support in end-jejunostomy short bowel syndrome (SBS) patients with intestinal failure (IF). Liraglutide, a glucagon-like peptide 1 receptor agonist, may reduce gastric hypersecretion and dampen gastric emptying, thereby improving conditions for intestinal absorption. MATERIALS AND METHODS: In an 8-week, open-label pilot study, liraglutide was given subcutaneously once daily to 8 end-jejunostomy patients, aged 63.4 ± 10.9 years (mean ± SD) and with small bowel lengths of 110 ± 66 cm. The 72-hour metabolic balance studies were performed before and at the end of treatment. Food intake was unrestricted. Oral fluid intake and parenteral support volume were kept constant. The primary end point was change in the ostomy wet weight output. RESULTS: Liraglutide reduced ostomy wet weight output by 474 ± 563 g/d from 3249 ± 1352 to 2775 ± 1187 g/d (P = .049, Student t test). Intestinal wet weight absorption tended to increase by 464 ± 557 g/d (P = .05), as did urine production by 765 ± 759 g/d (P = .02). Intestinal energy absorption improved by 902 ± 882 kJ/d (P = .02). CONCLUSION: Liraglutide reduced ostomy wet weight output in end-jejunostomy patients with SBS-IF and increased their intestinal wet weight and energy absorption. If larger, randomized, placebo-controlled studies confirm these effects, it adds to the hypothesis that many ileo-colonic brake hormones in conjunction may be involved in the process of intestinal adaptation. By identification of key hormones and addressing their potential synergistic effects, better treatments may be provided to patients with SBS-IF. This trial was registered at clinicaltrialsregister.eu as 2013-005499-16.

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.

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.