PPAR agonists as add-on treatment with metformin in management of type 2 diabetes: a systematic review and meta-analysis.

The combination of metformin and the peroxisome proliferator-activated receptors (PPAR) agonists offers a promising avenue for managing type 2 diabetes (T2D) through their potential complementary mechanisms of action. The results from randomized controlled trials (RCT) assessing the efficacy of PPAR agonists plus metformin versus metformin alone in T2D are inconsistent, which prompted the conduct of the systematic review and meta-analysis. We searched MEDLINE and EMBASE from inception (1966) to March 2023 to identify all RCTs comparing any PPAR agonists plus metformin versus metformin alone in T2D. Categorical variables were summarized as relative risk along with 95% confidence interval (CI). Twenty RCTs enrolling a total of 6058 patients met the inclusion criteria. The certainty of evidence ranged from moderate to very low. Pooled results show that using PPAR agonist plus metformin, as compared to metformin alone, results in lower concentrations of fasting glucose [MD = - 22.07 mg/dl (95% CI - 27.17, - 16.97), HbA1c [MD = - 0.53% (95% CI - 0.67, - 0.38)], HOMA-IR [MD = - 1.26 (95% CI - 2.16, - 0.37)], and fasting insulin [MD = - 19.83 pmol/L (95% CI - 29.54, - 10.13)] without significant increase in any adverse events. Thus, synthesized evidence from RCTs demonstrates the beneficial effects of PPAR agonist add-on treatment versus metformin alone in T2D patients. In particular, novel dual PPARα/γ agonist (tesaglitazar) demonstrate efficacy in improving glycaemic and lipid concentrations, so further RCTs should be performed to elucidate the long-term outcomes and safety profile of these novel combined and personalized therapeutic strategies in the management of T2D.PROSPERO registration no. CRD42023412603.

Metformin-Induced Chronic Diarrhea Misdiagnosed as Irritable Bowel Syndrome for Years.

Metformin is the most prescribed and recommended drug for type 2 diabetes mellitus because of its better tolerability, pleiotropic benefits, and cost-effectiveness. Metformin inhibits hepatic glucose production and increases muscle glucose uptake. Metformin is also associated with gastrointestinal side effects like abdominal bloating, flatulence, diarrhea, nausea, and vomiting. Metformin-related gastrointestinal side effects are mainly due to alteration in gut microbiota, raised intestinal glucose, and increased ileal bile salt reabsorption. We report a case of a 62-year-old diabetic patient who presented with chronic diarrhea with a weight loss of 6 kg from the last six years after initiation of metformin. He underwent multiple investigations and was finally misdiagnosed with irritable bowel syndrome for years. After discontinuation of metformin, there was a significant improvement in gastrointestinal symptoms. Our case highlights the importance of metformin-induced chronic diarrhea if no other causes for the diarrhea are obvious in patients with type 2 diabetes taking metformin. Consideration of this potential side effect of metformin must be valuable to avoid unwarranted investigations, additional drug therapy, and annoyance of the patients.

Characteristics and feeding intolerance in critically ill adult patients receiving peptide-based enteral nutrition: A retrospective cross-sectional study.

BACKGROUND & AIMS: Patients who experience gastrointestinal (GI) intolerance and hyperglycemia (or glucose intolerance) may not achieve appropriate caloric requirements and experience poor outcomes. The aim was to examine patient characteristics, disease severity, and enteral nutrition (EN) formula use in relation to feeding intolerance and healthcare resource utilization. METHODS: A retrospective, cross-sectional design using real-world data from PINC AI™ Healthcare Database, 2015-2019 was used. Critically ill hospitalized adults who required ≥3 days of 100% whey peptide-based EN, other peptide-based diets, or intact-protein standard and diabetic EN formulas were included. Primary outcomes were enteral feeding intolerance, including GI intolerance and hyperglycemia. Pairwise comparisons of other peptide-based and standard intact-protein groups with 100% whey-peptide were completed. Associations between EN group with GI intolerance and hyperglycemia, respectively, were evaluated via multivariable logistic regressions. RESULTS: Across 67 US hospitals, 19,679 inpatients (3242,100% whey-peptide, 3121 other peptide-based, and 13,316 standard intact-protein) were included. The 100% whey-peptide group had higher severity of illness and frequencies of comorbidities compared with other peptide-based and standard intact-protein groups. Hospital length of stay, intensive care unit stay, and 30-day readmission were similar across peptide-based cohorts. After controlling for demographic, visit, and severity characteristics, odds of GI intolerance were 18% higher for the other peptide-based group and 15% higher for the standard intact-protein group compared with the 100% whey-peptide group (each P < 0.03). In secondary analysis, odds of hyperglycemia were 81% higher for the other peptide-based group compared with the subgroup of very high-protein/low carbohydrate 100% whey-peptide (P < 0.001). CONCLUSIONS: Lower GI intolerance and greater glycemic control were associated with the use of 100% whey-peptide formulas relative to other formulas. Appropriate and optimal delivery of EN using specialized peptide-based formulas is a strategy to minimize feeding intolerance and benefit critically ill patients.

Management of iron deficiency in women of childbearing age with oral iron intolerance: a prospective, randomised, controlled trial of three doses of an iron-whey-protein formulation : Prospective RandomisEd study of women of Childbearing age with gastroInteStinal Intolerance to Oral iroN (PRECISION).

BACKGROUND: Nutritional deficit and oral iron gastrointestinal intolerance may be a common cause of iron deficiency, which can be managed by pharmacists. AIM: To understand the prevalence of iron deficiency in women of childbearing age with a self-reported history of intolerance to oral iron and the tolerability of three doses of an iron-whey-protein formulation in the care of these women. METHOD: Ferritin and haemoglobin levels were documented in women of childbearing age with oral iron gastrointestinal intolerance. In those with iron deficiency (ferritin < 30 µg/L), adherence, gastrointestinal tolerability, ferritin, transferrin saturation and haemoglobin levels were compared between their prior oral iron product and iron-whey-protein microspheres randomised to three doses (14 mg daily, 25 mg daily and 50 mg daily) for 12 weeks. RESULTS: Most screened women had low iron stores (128 (62.7%); ferritin < 30 µg/L), 65 (31.9%) had moderate to severe iron deficiency (ferritin < 12 µg/L) and 33 (16.2%) had iron deficiency anaemia (ferritin < 30 µg/L, haemoglobin < 12 g/dL). Amongst the 59 women who participated in the prospective clinical study of iron-whey-protein microspheres over 12 weeks, 48 (81.4%) were classified as adherent/persistent and fewer instances of gastrointestinal intolerance were reported (0.59 ± 0.91) when compared to 12 (20.3%) and (4.0 ± 2.2) respectively while taking the prior oral iron (Fisher's Exact and T-test respectively, both p < 0.001). There was no difference in adherence or tolerability of different iron-whey-protein formulation doses. Ferritin, haemoglobin and energy levels increased significantly over 12 weeks. CONCLUSION: Undiagnosed iron deficiency is common in women of childbearing age with a history of intolerance to oral iron and iron-whey-protein microspheres can improve adherence, GI tolerability, iron stores, haemoglobin and energy levels in these women. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier (registration includes full trial protocol): NCT04778072.

The co-regulation of the gut microbiome and host genes might play essential roles in metformin gastrointestinal intolerance.

Metformin is commonly used, but approximately 20% of patients experience gastrointestinal intolerance, leading to medication discontinuation for unclear reasons and a lack of effective management strategies. In this study, the 18 fecal and blood samples were analyzed using 16S rRNA and mRNA transcriptome, respectively. These samples included 3 fecal and 4 blood from metformin-tolerant T2D patients before and after metformin treatment (T and Ta), 3 fecal and 5 blood from metformin-intolerant T2D patients before and after treatment (TS and TSa), and 6 fecal samples from healthy controls. The results showed that certain anti-inflammatory gut bacteria and gene, such as Barnesiella (p = 0.046), Parabacteroides goldsteinii (p = 0.016), and the gene JUND (p = 0.0002), exhibited higher levels in metformin-intolerant patients, and which decreased after metformin treatment (p < 0.05). This potentially invalidates patients' anti-inflammatory effect and intestinal mucus barrier protection, which may lead to alterations in intestinal permeability, decreased gut barrier function, and gastrointestinal symptoms, including diarrhea, bloating, and nausea. After metformin treatment, primary bile acids (PBAs) production species: Weissella confusa, Weissella paramesenteroides, Lactobacillus brevis, and Lactobacillus plantarum increased (p < 0.05). The species converting PBAs to secondary bile acids (SBAs): Parabacteroides distasonis decreased (p < 0.05). This might result in accumulation of PBAs, which also may lead to anti-inflammatory gene JUND and SQSTM1 downregulated. In conclusion, this study suggests that metformin intolerance may be attributed to a decrease in anti-inflammatory-related flora and genes, and also alterations in PBAs accumulation-related flora. These findings open up possibilities for future research targeting gut flora and host genes to prevent metformin intolerance.

Growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula in infants with cow's milk protein allergy.

Objective: To evaluate growth, tolerance and safety outcomes with use of an extensively hydrolyzed casein-based formula (eHCF) in infants with cow's milk protein allergy (CMPA). Methods: A total of 226 infants (mean ± SD age: 106.5 ± 39.5 days, 52.7% were girls) with CMPA who received eHCF comprising at least half of the daily dietary intake were included. Data on anthropometrics [weight for age (WFA), length for age (LFA) and weight for length (WFL) z-scores] were recorded at baseline (visit 1), while data on infant feeding and stool records, anthropometrics and Infant Feeding and Stool Patterns and Formula Satisfaction Questionnaires were recorded at visit 2 (on Days 15 ± 5) and visit 3 (on Days 30 ± 5). Results: From baseline to visit 2 and visit 3, WFA z-scores (from -0.60 ± 1.13 to -0.54 ± 1.09 at visit 2, and to -0.44 ± 1.05 at visit 3, p < 0.001) and WFL z-scores (from -0.80 ± 1.30 to -0.71 ± 1.22 at visit 2, and to -0.64 ± 1.13 at visit 3, p = 0.002) were significantly increased. At least half of infants never experienced irritability or feeding refusal (55.7%) and spit-up after feeding (50.2%). The majority of mothers were satisfied with the study formula (93.2%), and wished to continue using it (92.2%). Conclusions: In conclusion, eHCF was well-accepted and tolerated by an intended use population of infants ≤ 6 months of age with CMPA and enabled adequate volume consumption and improved growth indices within 30 days of utilization alongside a favorable gastrointestinal tolerance and a high level of parental satisfaction.

Using Machine-Learning to Assess the Prognostic Value of Early Enteral Feeding Intolerance in Critically Ill Patients: A Retrospective Study.

BACKGROUND: The association between gastrointestinal intolerance during early enteral nutrition (EN) and adverse clinical outcomes in critically ill patients is controversial. We aimed to assess the prognostic value of enteral feeding intolerance (EFI) markers during early ICU stays and to predict early EN failure using a machine learning (ML) approach. METHODS: We performed a retrospective analysis of data from adult patients admitted to Beilinson Hospital ICU between January 2011 and December 2018 for more than 48 h and received EN. Clinical data, including demographics, severity scores, EFI markers, and medications, along with 72 h after admission, were analyzed by ML algorithms. Prediction performance was assessed by the area under the receiver operating characteristics (AUCROC) of a ten-fold cross-validation set. RESULTS: The datasets comprised 1584 patients. The means of the cross-validation AUCROCs for 90-day mortality and early EN failure were 0.73 (95% CI 0.71-0.75) and 0.71 (95% CI 0.67-0.74), respectively. Gastric residual volume above 250 mL on the second day was an important component of both prediction models. CONCLUSIONS: ML underlined the EFI markers that predict poor 90-day outcomes and early EN failure and supports early recognition of at-risk patients. Results have to be confirmed in further prospective and external validation studies.

Effects of combined treatment of probiotics and metformin in management of type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Lifestyle changes and dietary intervention, including the use of probiotics, can modulate dysbiosis of gut microbiome and contribute to the management of type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to assess the efficacy of metformin plus probiotics versus metformin alone on outcomes in patients with T2DM. METHODS: We searched MEDLINE and EMBASE from inception to February 2023 to identify all randomized controlled trials (RCTs), which compared the use of metformin plus probiotics versus metformin alone in adult patients with T2DM. Data were summarized as mean differences (MD) with 95 % confidence interval (CI) and pooled under the random effects model. FINDINGS: Fourteen RCTs (17 comparisons, 1009 patients) were included in this systematic review. Pooled results show a significant decrease in fasting glucose (FG) (MD = -0.64, 95 % CI = -1.06, -0.22) and HbA1c (MD = -0.29, 95 % CI = -0.47, -0.10) levels in patients with T2DM treated with metformin plus probiotics versus metformin alone. The addition of probiotics to metformin resulted in lower odds of gastrointestinal adverse events (Odds ratio = 0.18, 95 % CI = 0.09, 0.3.8; I2 = 0 %). CONCLUSIONS: The addition of probiotics to metformin therapy is associated with improvement in T2DM outcomes. However, high-quality and adequately reported RCTs are needed in the future to confirm our findings.

Intermittent bolus versus continuous feeding in children receiving an enteral formula with food derived ingredients: A national multicentre retrospective study.

BACKGROUND AND AIM: A perceived factor believed to have an impact on feed tolerance relates to the mode in which nutrition is delivered regarding intermittent bolus or continuous feeding. Enteral formulas with food derived ingredients have been developed to help address some of the many feeding issues experienced by children who are tube fed. This study aimed to evaluate the tolerance of different feeding modes in children who are fed with an enteral formula with food derived ingredients. METHODS: Data was collected by paediatric dietitians from dietetic records over a month period on children who had switched to an enteral formula with food derived ingredients. Data was inputted to a Microsoft form to capture the impact of varying modes of feeding (intermittent bolus/continuous/combination) on gastrointestinal and anthropometric outcomes. RESULTS: Forty-three children were recruited between March 2021 to July 2021 across four National Health Service Trusts. Children who were continuously fed saw the greatest reported improvement in retching, abdominal pain and loose stools. Children who were fed intermittent bolus reported the greatest increase in weight (p-value 0.003). Over 90% of dietitians reported nutritional goals were achieved after switching formula; children who were fed continuously reported the highest achievement to meet dietitian's nutritional goals. CONCLUSION: Enteral formulas with food derived ingredients are well tolerated and effective in achieving weight gain and meeting dietetic goals whether delivered continuously or as intermittent bolus feed. The clinical situation will determine the most appropriate and effective feeding mode and should be guided by the dietitian and medical team.

Perspective: Assessing Tolerance to Nondigestible Carbohydrate Consumption.

Human intestinal enzymes do not hydrolyze nondigestible carbohydrates (NDCs), and thus, they are not digested and absorbed in the small intestine. Instead, NDCs are partially to completely fermented by the intestinal microbiota. Select NDCs are associated with health benefits such as laxation and lowering of blood cholesterol and glucose. NDCs provide functional attributes to processed foods, including sugar or fat replacers, thickening agents, and bulking agents. Additionally, NDCs are incorporated into processed foods to increase their fiber content. Although consumption of NDCs can benefit health and contribute functional characteristics to foods, they can cause gastrointestinal symptoms, such as flatulence and bloating. As gastrointestinal symptoms negatively affect consumer well-being and their acceptance of foods containing NDC ingredients, it is crucial to consider tolerance when designing food products and testing their physiological health benefits in clinical trials. This perspective provides recommendations for the approach to assess gastrointestinal tolerance to NDCs, with a focus on study design, population criteria, intervention, comparator, and outcome. Special issues related to studies in children and implications for stakeholders are also discussed. It is recommended that the evaluation of gastrointestinal tolerance to NDCs be conducted in randomized, blinded, controlled crossover studies using standard gastrointestinal questionnaires, with attention to study participant background diets, health status, lifestyle, and medications.

The Effects of Enteral Nutrition in Critically Ill Patients with COVID-19: A Systematic Review and Meta-Analysis.

Background: Patients who are critically ill with COVID-19 could have impaired nutrient absorption due to disruption of the normal intestinal mucosa. They are often in a state of high inflammation, increased stress and catabolism as well as a significant increase in energy and protein requirements. Therefore, timely enteral nutrition support and the provision of optimal nutrients are essential in preventing malnutrition in these patients. Aim: This review aims to evaluate the effects of enteral nutrition in critically ill patients with COVID-19. Method: This systematic review and meta-analysis was conducted based on the preferred reporting items for systematic review and meta-Analysis framework and PICO. Searches were conducted in databases, including EMBASE, Health Research databases and Google Scholar. Searches were conducted from database inception until 3 February 2022. The reference lists of articles were also searched for relevant articles. Results: Seven articles were included in the systematic review, and four articles were included in the meta-analysis. Two distinct areas were identified from the results of the systematic review and meta-analysis: the impact of enteral nutrition and gastrointestinal intolerance associated with enteral nutrition. The impact of enteral nutrition was further sub-divided into early enteral nutrition versus delayed enteral nutrition and enteral nutrition versus parenteral nutrition. The results of the meta-analysis of the effects of enteral nutrition in critically ill patients with COVID-19 showed that, overall, enteral nutrition was effective in significantly reducing the risk of mortality in these patients compared with the control with a risk ratio of 0.89 (95% CI, 0.79, 0.99, p = 0.04). Following sub-group analysis, the early enteral nutrition group also showed a significant reduction in the risk of mortality with a risk ratio of 0.89 (95% CI, 0.79, 1.00, p = 0.05). The Relative Risk Reduction (RRR) of mortality in patients with COVID-19 by early enteral nutrition was 11%. There was a significant reduction in the Sequential Organ Failure Assessment (SOFA) score in the early enteral nutrition group compared with the delayed enteral nutrition group. There was no significant difference between enteral nutrition and parenteral nutrition in relation to mortality (RR = 0.87; 95% CI, 0.59, 1.28, p = 0.48). Concerning the length of hospital stay, length of ICU stay and days on mechanical ventilation, while there were reductions in the number of days in the enteral nutrition group compared to the control (delayed enteral nutrition or parenteral nutrition), the differences were not significant (p > 0.05). Conclusion: The results showed that early enteral nutrition significantly (p < 0.05) reduced the risk of mortality among critically ill patients with COVID-19. However, early enteral nutrition or enteral nutrition did not significantly (p > 0.05) reduce the length of hospital stay, length of ICU stay and days on mechanical ventilation compared to delayed enteral nutrition or parenteral nutrition. More studies are needed to examine the effect of early enteral nutrition in patients with COVID-19.

Prebiotic Supplementation in Kidney Transplant Recipients for Preventing Infections and Gastrointestinal Upset: A Randomized Controlled Feasibility Study.

OBJECTIVES: Modulating the large intestinal microbiome of kidney transplant recipients (KTRs) may reduce infectious complications. The aim of this study is to assess the feasibility of a randomized controlled trial of prebiotics in reducing infections and gastrointestinal symptoms in KTRs. (DESIGN) AND METHODS: Acute KTRs were recruited to a double-blind, placebo-controlled, randomized trial at a single kidney transplant center. Patients were provided with prebiotics or placebo for 7 weeks. The primary outcome was feasibility, defined as recruitment of ≥80% of eligible people within 6 months. Secondary outcomes included adherence and tolerability, participant retention in trial, proportions of participants providing serum and stool specimens, self-reported quality of life, gastrointestinal symptoms, and infection events. RESULTS: During the 7-week period, 72 patients met eligibility criteria, of whom 60 (83%) consented to participate (mean ± standard deviation age 53 ± 12 years; 62% males). Fifty-six (78%) participants were randomized (27 interventions and 29 controls). Although participants receiving intervention experienced reduced gastrointestinal symptoms (-0.28 [interquartile range, IQR -0.67 to 0.08] vs. -0.07 [IQR -0.27 to 0], P = .03), both control and intervention groups were similar in adherence (67% vs. 72%, P = .36), tolerability (56% vs. 62%, P = .64), quality of life (-0.2 [IQR -0.6 to 0] vs. -0.2 [IQR -0.8 to 0], P = .82), and infection events (33% vs. 34%, P = .83). Blood and stool samples were collected from ≥90% of participants in both groups. CONCLUSIONS: It is feasible to recruit and retain acute KTRs in a randomized, placebo-controlled trial examining the effect of prebiotics on infections and gastrointestinal symptoms. This study also showed that prebiotics significantly reduced gastrointestinal symptoms.

Monitor gastrointestinal tolerance in children who have switched to an "enteral formula with food-derived ingredients": A national, multicenter retrospective chart review (RICIMIX study).

BACKGROUND: Enteral tube feeding intolerances, such as diarrhea, are commonly reported in children. In the pediatric population, interest is growing in the use of blended diets for the management of enteral feeding intolerances. Fiber within a blended diet stimulates the growth of beneficial gut bacteria, which in turn produce short-chain fatty acids, which are utilized as energy substrates for enterocytes. Enteral formula manufacturers have responded to this trend towards "real-food" blended diets and developed an enteral formula with food-derived ingredients. The aim of this study was to collect data relating to feed tolerance in children who had switched to an "enteral formula with food-derived ingredients." METHODS: A national multicenter retrospective study. RESULTS: Dietitians collected data from 43 medically unwell children between March 2021 and July 2021. Significant improvements were reported in children who had switched to an "enteral formula with food-derived ingredients" in retching 17 of 18 children (95%), flatulence 6 of 8 children (85%), loose stools 10 of 11 children (90%), and constipation 10 of 11 children (90%). These improvements in gastrointestinal symptoms were reflected in weight change during the one month period measurements were collected (baseline, 19.5 kg [SD, 9]; 1 month, 20.1 kg [SD, 9]; P = 0.002). CONCLUSION: We have observed beneficial outcomes in medically complex children who have switched to an "enteral formula with food-derived ingredients." Our data should motivate healthcare professionals to implement more research to better evaluate the clinical impact and mechanisms of action of blended diets and enteral formulas with food-derived ingredients.

Safety and tolerance of enteral nutrition in COVID-19 critically ill patients, a retrospective study.

BACKGROUND: There is a lack of evidence about the tolerance of enteral nutrition (EN) in COVID-19 critically ill patients. However, several gastrointestinal manifestations related to COVID-19 have been described. The aims of this study were to analyze the incidence of gastrointestinal intolerance (GI) associated to EN (diarrhea, vomiting, gastroparesis and constipation) and to describe energy/protein provision along with biochemical alterations during the first week of EN. METHODS: A retrospective cohort of COVID-19 critically ill patients under mechanical ventilation. We reported daily enteral nutrition infusion and gastrointestinal manifestations within the first week of intubation and enteral nutrition initiation. RESULTS: Fifty-two patients were included; 40.3% were overweight and 46.2% were obese. During the first 7 days of EN, manifestations of GI intolerance such as vomiting, diarrhea and gastroparesis were present in 18 patients (32.4%). Hypernatremia (39%) was the most frequent electrolyte abnormality. Only Acute Kidney Injury (AKI) diagnosis was associated with a higher energy deficit on day 7. No associations between drug prescription and GI intolerance were observed. On day 4, 94.5% of patients were receiving more than 80% of energy requirements and 94.2% of protein requirements. Accumulated energy and protein deficits at day 3 were 2171.2 ± 945 kcal and 114.9 ± 49.2 g, respectively; and 2586.4 ± 1151 kcal, 133.3 ± 60.4 g at day 7. CONCLUSION: Enteral nutrition is feasible and well-tolerated in COVID-19 patients with mechanical ventilation within the first week of enteral nutrition initiation. More studies are needed to elucidate the impact of nutritional therapy on infection course and outcomes.

Metformin extended-release versus metformin immediate-release for adults with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.

AIM: To compare the efficacy and tolerability of metformin extended-release (MXR) and the conventional metformin immediate-release (MIR) formulations in adults with type 2 diabetes mellitus (T2DM) METHODS: PubMed, the Cochrane Library, ClinicalTrials.gov and other sources were searched until 19 March 2021 for randomized controlled trials (RCTs) that compared equal daily doses of MXR and MIR in adults with T2DM. Random-effects model meta-analysis was performed to obtain pooled mean difference (MD) of change from baseline for continuous outcomes and risk ratio (RR) for dichotomous outcomes. Primary outcomes considered were HbA1c and key gastrointestinal (GI) symptoms (abdominal discomfort or pain, diarrhea, dyspepsia, and nausea & vomiting). RESULTS: Nine RCTs that randomized a total of 2609 adults revealed that MIR was statistically associated with better HbA1c lowering (MD 0.09% [95% confidence interval or CI, 0.01%, 0.17%]), MXR only reduced dyspepsia (RR 0.58 [95% CI, 0.34, 0.98]), and both formulations were associated with similar cumulative incidence of other key GI symptoms. CONCLUSIONS: MXR was associated with statistically worse but likely clinically similar HbA1c lowering and minimal improvement of GI intolerance compared to MIR. Protocol Registration: PROSPERO (CRD42019148008).

Milk Containing A2 ß-Casein ONLY, as a Single Meal, Causes Fewer Symptoms of Lactose Intolerance than Milk Containing A1 and A2 ß-Caseins in Subjects with Lactose Maldigestion and Intolerance: A Randomized, Double-Blind, Crossover Trial.

Acute-feeding and multiple-day studies have demonstrated that milk containing A2 ß-casein only causes fewer symptoms of lactose intolerance (LI) than milk containing both A1 and A2 ß-caseins. We conducted a single-meal study to evaluate the gastrointestinal (GI) tolerance of milk containing different concentrations of A1 and A2 ß-casein proteins. This was a randomized, double-blind, crossover trial in 25 LI subjects with maldigestion and an additional eight lactose maldigesters who did not meet the QLCSS criteria. Subjects received each of four types of milk (milk containing A2 ß-casein protein only, Jersey milk, conventional milk, and lactose-free milk) after overnight fasting. Symptoms of GI intolerance and breath hydrogen concentrations were analyzed for 6 h after ingestion of each type of milk. In an analysis of the 25 LI subjects, total symptom score for abdominal pain was lower following consumption of milk containing A2 ß-casein only, compared with conventional milk (p = 0.004). Post hoc analysis with lactose maldigesters revealed statistically significantly improved symptom scores (p = 0.04) and lower hydrogen production (p = 0.04) following consumption of milk containing A2 ß-casein only compared with conventional milk. Consumption of milk containing A2 ß-casein only is associated with fewer GI symptoms than consumption of conventional milk in lactose maldigesters.

Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.

Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.

Perioperative Enteral Nutrition After Left Ventricular Assist Device Implantation.

OBJECTIVE: We assessed what predicts nutritional adequacy at day 14 following implantation of left ventricular assist device (LVAD). METHOD: We retrospectively reviewed the cases of 97 adult patients who underwent LVAD implantation at our institution from June 2011 to June 2016. We divided the patients into two groups based on the administered enteral nutrition (EN) calories on post-operative day (POD) 14: the EN calories of group SEN (sufficient enteral nutrition) were >80% of their total target calories, or the EN calories of group IEN (insufficient enteral nutrition) were <80% of their total target calories. We compared the two groups in terms of the perioperative factors within 1 week after surgery. RESULTS: Groups SEN and IEN consisted of 53 and 44 patients, respectively. The mean doses of adrenaline and noradrenaline, mean central venous pressure (CVP), duration of nitric oxide administration, and mean residual gastric volume during 1 week after surgery in group SEN were significantly lower than those in group IEN (P < .05). In multivariate analysis, higher CVP during 1 week after surgery was identified as an independent risk factor for delayed EN on POD14 (odds ratio, 1.40; 95% confidence interval, 1.11-1.66; P = .0037). Total bilirubin, occurrence of acute kidney injury, and mixed venous blood saturation during 1 week after surgery were not significant predictors for EN on POD14. CONCLUSIONS: Increased CVP within 1 week after LVAD implantation was an independent factor for reduced EN feeding.

Early introduction of a semi-elemental formula may be cost saving compared to a polymeric formula among critically ill patients requiring enteral nutrition: a cohort cost-consequence model.

OBJECTIVES: Gastrointestinal (GI) intolerance is associated with adverse outcomes in critically ill patients receiving enteral nutrition (EN). The objective of this analysis is to quantify the cost of GI intolerance and the cost implications of starting with semi-elemental EN in intensive care units (ICUs). STUDY DESIGN: A US-based cost-consequence model was developed to compare the costs for patients with and without GI intolerance and the costs with semi-elemental or standard EN while varying the proportion of GI intolerance cases avoided. MATERIALS AND METHODS: ICU data on GI intolerance prevalence and outcomes in patients receiving EN were derived from an observational study. ICU stay costs were obtained from literature and the costs of EN from US customers' price lists. The model was used to conduct a threshold analysis, which calculated the minimum number of cases of GI intolerance that would have to be avoided to make the initial use of semi-elemental formula cost saving for the cohort. RESULTS: Out of 100 patients receiving EN, 31 had GI intolerance requiring a median ICU stay of 14.4 days versus 11.3 days for each patient without GI intolerance. The model calculated that semi-elemental formula was cost saving versus standard formula when only three cases of GI intolerance were prevented per 100 patients (7% of GI intolerance cases avoided). CONCLUSION: In the US setting, the model predicts that initial use of semi-elemental instead of standard EN can result in cost savings through the reduction in length of ICU stay if >7% of GI intolerance cases are avoided.

Retrospective evaluation of the impact of early enteral nutrition on clinical outcomes in dogs with pancreatitis: 34 cases (2010-2013).

OBJECTIVE: To evaluate the effect of early enteral nutritional therapy on time to return to voluntary intake, maximum food consumption, incidence of gastrointestinal intolerance (GI), and total hospitalization time for dogs with acute pancreatitis. DESIGN AND SETTING: Retrospective analysis of dogs with pancreatitis at a veterinary teaching hospital between 2010 and 2013. ANIMALS: Thirty-four client-owned dogs diagnosed with acute or acute-on-chronic pancreatitis. PROCEDURES AND INTERVENTIONS: Medical records of dogs evaluated for inappetence, anorexia, and GI for which a diagnosis of pancreatitis was recorded were reviewed. The time to initiation of food offerings since hospitalization were recorded in addition to signalment, historical medical conditions, chief complaint, physical examination findings, diagnostic results, treatments provided, timing of food offering (within 48 h of hospitalization, early feeding group (EFG) versus delayed feeding group (DFG), diet therapy (low fat versus high fat), caloric intake (% resting energy requirement), incidence of GI (%), and length of hospitalization (LOH) (days). A Clinical Severity Index Score (CSIS) was determined for each patient. MEASUREMENTS AND MAIN RESULTS: Dogs in the EFG demonstrated a decreased time to return of voluntary intake (2.1 days, EFG versus 2.7 days, DFG; P = 0.05) and time (days) to maximum intake (3, EFG versus 3.4 DFG) as compared to the DFG dogs. The DFG exhibited more GI versus EFG irrespective of CSIS grouping (60% versus 26%, P = 0.04). A CSIS ≥ 7 was associated with prolonged LOH (P = 0.004); however, time to initiation of feeding and diet selection did not impact LOH (P = 0.8). CONCLUSIONS AND CLINICAL RELEVANCE: Results of the study suggested that feeding within 48 hours of hospitalization for canine pancreatitis has a positive impact on return to voluntary intake and decreases the frequency of GI in these patients, independent of CSIS. The traditional protocol of withholding food during hospitalization may not be necessary nor yield the most benefit for patient recovery; subsequently early enteral refeeding should be considered.