Investigation and Management of Stool Frequency and Consistency Associated With SGLT1 Inhibition by Reducing Dietary Carbohydrate: A Randomized Trial.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

SMOFlipid Protects Preterm Neonates against Perinatal Nutrition-Associated Cholestasis.

OBJECTIVE: Intravenous lipid infusions improve both short- and long-term outcomes of premature neonates. However, prolonged infusion of lipids has been implicated in the development of parenteral nutrition-associated cholestasis (PNAC). We speculated that the multicomponent SMOFlipid would be hepatoprotective against PNAC. STUDY DESIGN: This is a retrospective review comparing the incidence and severity of direct hyperbilirubinemia in preterm infants <1,500 g who were hospitalized for a minimum of 2 weeks during a 20-month period in which all preterm infants on total parenteral nutrition (TPN) received fat as Lipofundin with the following 20-month period in which all preterm infants on TPN received SMOFlipid. RESULTS: Infants in the SMOFlipid period had a lower incidence of PNAC (6 vs. 13%; p = 0.022), lower peak direct bilirubin levels (3.2 vs. 7.1 mg/dL; p = 0.018), and a shorter length of stay (51 vs. 60 days; p = 0.019). The relative risk of developing direct hyperbilirubinemia during the Lipofundin period was 2.22 (1.1-4.3) as compared with period 1; p = 0.018; NNT-14. CONCLUSION: SMOFlipid was hepatoprotective in our population of preterm neonates <1,500 g receiving long-term TPN as compared with those receiving Lipofundin, despite similar levels of exposure to both intravenous lipid load and duration in the two groups.

Home parenteral nutrition with an omega-3-fatty-acid-enriched MCT/LCT lipid emulsion in patients with chronic intestinal failure (the HOME study): study protocol for a randomized, controlled, multicenter, international clinical trial.

BACKGROUND: Home parenteral nutrition (HPN) is a life-preserving therapy for patients with chronic intestinal failure (CIF) indicated for patients who cannot achieve their nutritional requirements by enteral intake. Intravenously administered lipid emulsions (ILEs) are an essential component of HPN, providing energy and essential fatty acids, but can become a risk factor for intestinal-failure-associated liver disease (IFALD). In HPN patients, major effort is taken in the prevention of IFALD. Novel ILEs containing a proportion of omega-3 polyunsaturated fatty acids (n-3 PUFA) could be of benefit, but the data on the use of n-3 PUFA in HPN patients are still limited. METHODS/DESIGN: The HOME study is a prospective, randomized, controlled, double-blind, multicenter, international clinical trial conducted in European hospitals that treat HPN patients. A total of 160 patients (80 per group) will be randomly assigned to receive the n-3 PUFA-enriched medium/long-chain triglyceride (MCT/LCT) ILE (Lipidem/Lipoplus® 200 mg/ml, B. Braun Melsungen AG) or the MCT/LCT ILE (Lipofundin® MCT/LCT/Medialipide® 20%, B. Braun Melsungen AG) for a projected period of 8 weeks. The primary endpoint is the combined change of liver function parameters (total bilirubin, aspartate transaminase and alanine transaminase) from baseline to final visit. Secondary objectives are the further evaluation of the safety and tolerability as well as the efficacy of the ILEs. DISCUSSION: Currently, there are only very few randomized controlled trials (RCTs) investigating the use of ILEs in HPN, and there are very few data at all on the use of n-3 PUFAs. The working hypothesis is that n-3 PUFA-enriched ILE is safe and well-tolerated especially with regard to liver function in patients requiring HPN. The expected outcome is to provide reliable data to support this thesis thanks to a considerable number of CIF patients, consequently to broaden the present evidence on the use of ILEs in HPN. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03282955. Registered on 14 September 2017.

Colitis induced by sodium polystyrene sulfonate in sorbitol: A report of six cases.

Drug-related injury has been noted in virtually all organ systems, and recognition of the patterns of injury associated with medication enables modification of treatment and reduces the morbidity associated with the side effects of drugs. With the large number of new drugs being developed, documentation of the morphology of the changes seen as an adverse effect becomes important to characterize the pattern of injury. The pathologist is often the first to identify these abnormalities and correlate them with a particular drug. Kayexalate or sodium polystyrene sulfonate (SPS), a linear polymer derived from polystyrene containing sulfonic acid and sulfonate functional groups is used to treat hyperkalemia. It is usually administered with an osmotic laxative sorbitol orally or as retention enema. This combination has been implicated in causing damage to different parts of the gastrointestinal (GI) tract especially the colon and causes an established pattern of injury, recognizable by the presence of characteristic crystals, is presented to create a greater awareness of the Kayexalate colitis. This entity should be included in the differential diagnosis of lower GI mucosal injury in a setting of uremia and hyperkalemia.

Colon Necrosis Due to Sodium Polystyrene Sulfonate with and without Sorbitol: An Experimental Study in Rats.

INTRODUCTION: Based on a single rat study by Lillemoe et al, the consensus has been formed to implicate sorbitol rather than sodium polystyrene sulfonate (SPS) as the culprit for colon necrosis in humans treated with SPS and sorbitol. We tested the hypothesis that colon necrosis by sorbitol in the experiment was due to the high osmolality and volume of sorbitol rather than its chemical nature. METHODS: 26 rats underwent 5/6 nephrectomy. They were divided into 6 groups and given enema solutions under anesthesia (normal saline, 33% sorbitol, 33% mannitol, SPS in 33% sorbitol, SPS in normal saline, and SPS in distilled water). They were sacrificed after 48 hours of enema administration or earlier if they were very sick. The gross appearance of the colon was visually inspected, and then sliced colon tissues were examined under light microscopy. RESULTS: 1 rat from the sorbitol and 1 from the mannitol group had foci of ischemic colonic changes. The rats receiving SPS enema, in sorbitol, normal saline, distilled water, had crystal deposition with colonic necrosis and mucosal erosion. All the rats not given SPS survived until sacrificed at 48 h whereas 11 of 13 rats that received SPS in sorbitol, normal saline or distilled water died or were clearly dying and sacrificed sooner. There was no difference between sorbitol and mannitol when given without SPS. CONCLUSIONS: In a surgical uremic rat model, SPS enema given alone or with sorbitol or mannitol seemed to cause colon necrosis and high mortality rate, whereas 33% sorbitol without SPS did not.

Ileum and colon perforation following peritoneal dialysis-related peritonitis and high-dose calcium polystyrene sulfonate.

A rare but severe complication, intestinal necrosis, has been reported after sodium polystyrene sulfonate (SPS; Kayexalate) and sorbitol intake. Some case reports described bowel perforation following calcium polystyrene sulfonate (CPS; Kalimate) administration. We report a case of ileum and colon perforation following peritoneal dialysis-related peritonitis and high-dose Kalimate in a 59-year-old female patient. The patient had a history of hypertension, diabetes mellitus, and end-stage renal disease (ESRD). During hospitalization for peritoneal dialysis-related peritonitis, she developed hyperkalemia, and Kalimate was administered orally. However, severe abdominal distension and pain occurred just one day after Kalimate intake. An urgent surgery disclosed several perforations in the ileum and sigmoid colon. Pathology of the resected gut showed transmural necrosis and perforation with basophilic angulated crystals. The patient finally expired during hospitalization due to refractory septic shock.

Impact of new-generation lipid emulsions on cellular mechanisms of parenteral nutrition-associated liver disease.

Parenteral nutrition (PN) is a life-saving nutritional support for a large population of hospitalized infants, and lipids make a substantial contribution to their energy and essential fatty acid (FA) needs. A challenge in the care of these infants is that their metabolic needs require prolonged PN support that increases the risk of PN-associated liver disease (PNALD). In recent years, the emergence of new parenteral lipid emulsions containing different source lipids and FA profiles has created nutritional alternatives to the first-generation, soybean oil-based lipid emulsion Intralipid. The limited U.S. introduction of the new-generation fish-oil emulsion Omegaven has generated promising results in infants with PNALD and spawned a renewed interest in how PN and lipid emulsions, in particular, contribute to this disease. Studies suggest that the lipid load and constituents, such as specific FAs, ratio of n-3 (ω-3) to n-6 (ω-6) long-chain polyunsaturated FAs, phytosterols, and vitamin E content, may be involved. There is an existing literature describing the molecular mechanisms whereby these specific nutrients affect hepatic metabolism and function via lipid and bile acid sensing nuclear receptors, such as peroxisome proliferator-activated receptor α, liver X receptor, and farnesoid X receptor, yet virtually no information as to how they interact and modulate liver function in the context of PN in pediatric patients or animal models. This article will review the recent development of parenteral lipid emulsions and their influence on PNALD and highlight some of the emerging molecular mechanisms that may explain the effects on liver function and disease.

Damned if you do, damned if you don't: potassium binding resins in hyperkalemia.

Sodium polystyrene sulfonate (SPS) potassium binding resins increase colonic potassium excretion and are approved by the U.S. Food and Drug Administration (FDA) for the treatment of hyperkalemia. In 2009, the FDA recommended that sorbitol, a cathartic often given with SPS to prevent obstipation, not be added to SPS powder because of associated colonic necrosis. A premixed oral suspension of SPS in 33% sorbitol was not included in this warning. SPS resins increase stool potassium excretion in normokalemic subjects, but proportionately more potassium is excreted due to cathartics when the two are combined. In hyperkalemic patients, oral SPS mixed in water significantly decreases serum potassium within 24 hours. SPS/sorbitol-associated colonic necrosis is most commonly seen in patients who have received enemas in the setting of recent abdominal surgery, bowel injury, or intestinal dysfunction. It is a rare event, on the order of 0.2 to 0.3%, almost exclusively present in patients at risk. The agent most likely associated with colonic necrosis is 70% sorbitol, and animal data support that etiology. There is very little data to suggest that oral SPS given with 33% sorbitol (in the premixed form) or SPS powder in water orally or as an enema causes colonic necrosis. SPS ion-exchange resins are the only agents, other than dialysis and diuretics, available to increase potassium excretion in hyperkalemia, and when used appropriately, they appear to be clinically effective and reasonably safe.

Ileocolic perforation secondary to sodium polystyrene sulfonate in sorbitol use: a case report.

Hyperkalemia is a common condition encountered in medical and surgical patients. It can lead to various complications including cardiac arrhythmias. Sodium polystyrene sulfonate (SPS) in sorbitol is an ion-exchange resin that can be used to treat hyperkalemia. It can be used in enema or in oral form. The present article describes the case of an intensive care unit patient who experienced severe, diffuse, intestinal perforation induced by the use of SPS-sorbitol, requiring multiple laparotomies, followed by a brief review of the relevant literature and recommendations regarding the use of SPS-sorbitol.

The role of diet in symptoms of irritable bowel syndrome in adults: a narrative review.

This review summarizes what is known about the effect of diet on irritable bowel syndrome (IBS) symptoms emphasizing data from randomized, controlled clinical trials. Studies suggest that IBS symptoms in one quarter of patients may be caused or exacerbated by one or more dietary components. Recent studies indicate that a diet restricted in fermentable, poorly absorbed carbohydrates, including fructose, fructans (present in wheat and onions), sorbitol, and other sugar alcohols is beneficial, but confirmatory studies are needed. Despite a long history of enthusiastic use, fiber is marginally beneficial. Insoluble fiber may worsen symptoms. Some patients with IBS, especially those with constipation, will improve with increased intake of soluble fiber. Prebiotic fibers have not been adequately tested. Daily use of peppermint oil is effective in relieving IBS symptoms. The usefulness of probiotics in the form of foods such as live-culture yogurt and buttermilk for IBS symptoms is not established. In clinical practice, it is very difficult to establish that a patient's symptoms result from an adverse reaction to food. A double blind placebo-controlled food challenge is the most reliable method, but it is not suitable for routine clinical use. A modified exclusion diet and stepwise reintroduction of foods or trials of eliminating classes of food may be useful.

Does hepatomegaly alter iron-dependent oxidative effects in human plasma?

A four-fold increase in the iron content of normal subjects was detected in plasma after 5 hours of iron administration. Iron supplementation had a surprisingly erratic effect on four patients with hepatomegaly secondary to heart insufficiency, since the increase in the iron content in the plasma after iron-dextran administration was either within the control range or significantly lower, independently of the initial values. Thiobarbituric acid reactive substances (TBARS) content was 2.5 +/- 0.2 and 4.3 +/- 0.4 microM for control and hepatomegalic subjects, respectively. The TBARS basal level was increased by iron supplementation. The difference between TBARS content in hepatomegalic and control subjects, after 5 hours of iron administration, was increased by 50% as compared to the difference in the basal content of TBARS. alpha-Tocopherol (alpha-T) content in plasma from subjects with hepatomegaly showed a significant decrease (-41%) as compared to control subjects. No significant difference over the basal level of alpha-T was measured after 5 hours of iron administration in any subject. The data presented here suggest that abnormal liver condition affects iron-dependent oxidative stress in plasma. Moreover, alpha-T does not seem to be the main antioxidant to control iron-dependent oxidative stress in plasma.

Intestinal necrosis following Calcium Resonium-sorbitol administration in a premature uraemic infant.

Sodium polystyrene sulphonate (Resonium A) in sorbitol given as an enema or orally to treat hyperkalaemia has been described to induce intestinal necrosis in uraemic patients. We report a case of a premature infant with acute renal insufficiency who developed focal transmural necrosis and perforation of the small intestine after 10 days of administration of calcium polystyrene sulphonatum (Calcium Resonium) in sorbitol by enema and by nasogastric tube. On histological examination of the resected part of the small intestine, numerous strongly basophilic angular crystals of resonium were found in the lumen, in the necrotic wall, as well as in the organized exudate on the peritoneal surface. The crystals showed a strong direct Schiff positivity without preoxidation. They were also stained using PAS, Giemsa, Ziehl-Neelsen, Schmorl, and Gram method. In contrast, the crystals were Congo red and Alcian blue (pH 2.5) negative and non-birefringent. The direct Schiff positivity without preoxidation is virtually pathognomonic for resin crystals in routinely processed tissues. The same crystals were observed in the lumen of the small intestine and in peritoneal adhesions at autopsy. Thus our case provides additional evidence that Resonium A/Calcium Resonium in sorbitol administered as an enema or orally can lead to intestinal necrosis in uraemic patients.

Another feature of TURP syndrome: hyperglycaemia and lactic acidosis caused by massive absorption of sorbitol.

Endoscopic transurethral resection of the prostate (TURP) can be complicated by absorption of a large volume of irrigation fluid. The clinical features of this complication are referred as the TURP syndrome. We report a case where hyperglycaemia and lactic acidosis complicated the TURP syndrome caused by the massive absorption (approximately 15 litres) of a sorbitol- mannitol irrigation solution. The proposed mechanism is a type B lactic acidosis related to the metabolism of sorbitol.

Safety aspects of parenteral iron in patients with end-stage renal disease.

Absolute and functional iron deficiency is the most common cause of epoetin (recombinant human erythropoietin) hyporesponsiveness in renal failure patients. Diagnostic procedures for determining iron deficiency include measurement of serum iron levels, serum ferritin levels, saturation of transferrin and percentage of hypochromic red blood cells. Patients with iron deficiency should receive supplemental iron, either orally or intravenously. Adequate intravenous iron supplementation allows reduction of epoetin dosage by approximately 40%. Intravenous iron supplementation is recommended for all patients undergoing haemodialysis and for pre-dialysis and peritoneal dialysis patients with severe iron deficiency. During the maintenance phase (period of epoetin therapy after correction of iron deficiency), the use of low-dose intravenous iron supplementation (10 to 20 mg per haemodialysis treatment or 100 mg every second week) avoids iron overtreatment and minimises potential adverse effects. Depending on the degree of pre-existing iron deficiency, markedly higher iron doses are necessary during the correction phase (period of epoetin therapy after correction of iron deficiency) [e.g. intravenous iron 40 to 100 mg per haemodialysis session up to a total dose of 1000 mg]. The iron status should be monitored monthly during the correction phase and every 3 months during the maintenance phase to avoid overtreatment with intravenous iron.

Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition.

Sodium polystyrene sulfonate (Kayexalate) in sorbitol given as an enema or orally to treat hyperkalemia has been reported to induce intestinal necrosis in uremic patients. We studied the clinical and pathologic features of 15 patients in whom Kayexalate crystals were observed in specimens from gastrointestinal surgical resections (n = 9) or endoscopic biopsies (n = 7). Oral or nasogastric tube administration of Kayexalate in sorbitol was documented in 10 patients. Among 12 patients with colorectal specimens, necrosis was observed in nine patients (75%), represented by seven of eight surgical resection specimens and three of five endoscopic biopsy specimens. No other cause of colorectal necrosis apart from Kayexalate in sorbitol was apparent in seven patients, and four also had necrosis of the small intestine. Four patients with colonic necrosis in their initial resection specimen developed progressive necrosis of the small intestine or rectum, and five patients (56%) had fatal outcome within 1 day to 6 weeks. Kayexalate crystals were observed in upper gastrointestinal tract specimens from four patients, including one with hemorrhagic gastritis. Our findings provide additional evidence that Kayexalate in sorbitol administered orally or by nasogastric tube can produce necrosis in the gastrointestinal tract.

Role of iron and iron chelation therapy in oxygen free radical mediated tissue injury in an ascending mouse model of chronic pyelonephritis.

The contribution of iron towards the free radical generation leading to renal tissue damage was assessed using a non-obstructive ascending mouse model for chronic pyelonephritis. The parameters studied include luminol dependent chemiluminescence (LDCL), histopathology and some biochemical investigations. We found that iron enhanced the renal tissue damage and led to renal scarring, and end point in chronic renal inflammation, irrespective of the bacterial strain studied. In addition a role of iron chelation therapy as a treatment for chronic renal inflammation is also suggested.

Survival after high-dose intravenous infusion of irrigating fluids in the mouse.

OBJECTIVES: Fluid absorption is still a potentially fatal complication in patients undergoing transurethral resection of the prostate. We induced experimental overhydration in animals to find out which of three widely used irrigating fluids is most strongly associated with survival. METHODS: The survival and incidence of voiding was studied in 120 mice after an intravenous infusion of either 225, 250, 275, or 300 mL/kg of glycine 1.5%, mannitol 5%, or sorbitol 2% plus mannitol 1% over 60 minutes. RESULTS: Only 20% of the animals survived the glycine solution, whereas the overall survival rate after mannitol was 60%. The corresponding figure for sorbitol plus mannitol was 32%. Logistic regression analysis showed that survival was significantly more likely after infusion of mannitol 5% compared with the other irrigating fluids. The likelihood of survival was also higher in the animals in which the infusion induced diuresis and when the smaller volumes of irrigating fluid were given. CONCLUSIONS: Mannitol 5% offered the best chance of survival.