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Efficacy and Safety of Enteral Recombinant Human Insulin for Reduction of Time-to-Full Enteral Feeding in Preterm Infants: A Randomized, Double-blind, Placebo-Controlled Trial.
Shehadeh, N, Simmonds, A, Zangen, S, Riskin, A, Shamir, R
The Israel Medical Association journal : IMAJ. 2021;(9):563-568
Abstract
BACKGROUND Infants born very prematurely have functionally and structurally immature gastrointestinal tracts. OBJECTIVES To assess the safety and tolerability of administration of enteral recombinant human (rh) insulin on formula fed preterm infants and to assess whether enteral administration of rh-insulin enhances gastrointestinal tract maturation by reducing the time to reach full enteral feeding. METHODS A phase 2, multicenter, double-blind, placebo-controlled, randomized study was conducted. Premature infants (26-33 weeks gestation) were randomized 1:1 to receive insulin 400 μU/ml mixed with enteral feeding or placebo added to their formula. The primary efficacy outcome measure was the number of days required to achieve full enteral feeding. Safety outcomes included adverse events and blood glucose levels. RESULTS The study consisted of 33 infants randomized for the safety population and 31 for efficacy analysis. The mean time to full enteral feeding was 6.37 days (95% confidence interval [95%CI] 4.59-8.15) in the enteral rh-insulin treatment group (n=16) and 8.00 days (95%CI 6.20-9.80) in the placebo group (n=15), which represents a statistically significant reduction of 1.63 days (95%CI 0.29-2.97; P = 0.023). There was no difference in blood glucose levels between the groups and none of the participants experienced hypoglycemia. Adverse events occurred in 9/17 (53%) infants in the enteral rh-insulin group and 12/16 (75%) in the placebo group. CONCLUSIONS Our trial demonstrated that administration of enteral rh-insulin as supplement to enteral nutrition significantly reduced time to achieve full enteral feeding in preterm infants with a gestational age of 26-33 weeks.
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Chyme Reinfusion Restores the Regulatory Bile Salt-FGF19 Axis in Patients With Intestinal Failure.
Koelfat, KVK, Picot, D, Chang, X, Desille-Dugast, M, van Eijk, HM, van Kuijk, SMJ, Lenicek, M, Layec, S, Carsin, M, Dussaulx, L, et al
Hepatology (Baltimore, Md.). 2021;(5):2670-2683
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Abstract
BACKGROUND AND AIMS Automated chyme reinfusion (CR) in patients with intestinal failure (IF) and a temporary double enterostomy (TDE) restores intestinal function and protects against liver injury, but the mechanisms are incompletely understood. The aim was to investigate whether the beneficial effects of CR relate to functional recovery of enterohepatic signaling through the bile salt-FGF19 axis. APPROACH AND RESULTS Blood samples were collected from 12 patients, 3 days before, at start, and 1, 3, 5, and 7 weeks after CR initiation. Plasma FGF19, total bile salts (TBS), 7-α-hydroxy-4-cholesten-3-one (C4; a marker of bile salt synthesis), citrulline (CIT), bile salt composition, liver tests, and nutritional risk indices were determined. Paired small bowel biopsies prior to CR and after 21 days were taken, and genes related to bile salt homeostasis and enterocyte function were assessed. CR induced an increase in plasma FGF19 and decreased C4 levels, indicating restored regulation of bile salt synthesis through endocrine FGF19 action. TBS remained unaltered during CR. Intestinal farnesoid X receptor was up-regulated after 21 days of CR. Secondary and deconjugated bile salt fractions were increased after CR, reflecting restored microbial metabolism of host bile salts. Furthermore, CIT and albumin levels gradually rose after CR, while abnormal serum liver tests normalized after CR, indicating restored intestinal function, improved nutritional status, and amelioration of liver injury. CR increased gene transcripts related to enterocyte number, carbohydrate handling, and bile salt homeostasis. Finally, the reciprocal FGF19/C4 response after 7 days predicted the plasma CIT time course. CONCLUSIONS CR in patients with IF-TDE restored bile salt-FGF19 signaling and improved gut-liver function. Beneficial effects of CR are partly mediated by recovery of the bile salt-FGF19 axis and subsequent homeostatic regulation of bile salt synthesis.
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Inducing ketogenesis via an enteral formulation in patients with acute brain injury:a phase II study.
White, H, Venkatesh, B, Jones, M, Kruger, PS, Walsham, J, Fuentes, H
Neurological research. 2020;(4):275-285
Abstract
Objective: Although extensively studied in children, the safety and tolerability of ketone supplementation in adults is unclear, particularly in the acute brain injury population. The purpose of this study was to examine the feasibility and safety of inducing ketosis using an enteric ketogenic formulation and determine its impact on intracranial and cerebral perfusion pressures and metabolic parameters.Methods: Prospective interventional Phase II trial of ventilated critically ill patients with acute brain injury administered a ketogenic feed over a 6 day period.Results: 20 patients were recruited, 5 females and 15 males, 3 with stroke, 2 with subarachnoid haemorrhage and 15 with traumatic brain injury. Feeds were well tolerated with 19 patients completing study. There was a significant increase in both plasma beta-hydroxybutyrate and acetoacetate from 0.24± 0.31 mmol/l and 0.19 ± 0.16 mmol/l to 0.61 ± 0.53 mmol/l (p =0.0005) and 0.52 ± 0.40 mmol/l (p<0.0001) respectively over the 6 day period. Total daily Ketocal® caloric intake was positively correlated with plasma beta-hydroxybutyrate concentrations (p=0.0011). There was no significant correlation between the cerebral hypertension and cerebral hypoperfusion indices and plasma ketone concentrations. In 95% of patients there were no clinically significant changes in acid/base status over the 6 days with pH remaining within normal range.Conclusion: In patients with acute brain injury, an enterally administered ketogenic formulation increased plasma ketone concentrations, was well tolerated, did not impact on cerebral hemodynamics and can be safely administered.Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN12616000332426)Abbreviations: BHB: betahydroxybutyrate; AcAc: acetoacetate; ABI: acute brain injury; TBI: traumatic brain injury; CSF: cerebrospinal fluid; SAH: subarachnoid injury; CVA: cerebrovascular accidents; ICP: intracranial pressure; CPP: cerebral perfusion pressure; ICU: intensive care unit; EVD: external ventricular device; CHI: cerebral hypoperfusion index; IHI: intracranial hypertension index; GCS: Glasgow Coma Scale.
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Effect of Intermittent or Continuous Feed on Muscle Wasting in Critical Illness: A Phase 2 Clinical Trial.
McNelly, AS, Bear, DE, Connolly, BA, Arbane, G, Allum, L, Tarbhai, A, Cooper, JA, Hopkins, PA, Wise, MP, Brealey, D, et al
Chest. 2020;(1):183-194
Abstract
BACKGROUND Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. RESEARCH QUESTION Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? STUDY DESIGN AND METHODS In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. RESULTS Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 μM [44-98 μM]; P = .547) and trial day 10 (239 μM [33-444 μM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups. INTERPRETATION Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov.
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Promotion of Regular Oesophageal Motility to Prevent Regurgitation and Enhance Nutrition Intake in Long-Stay ICU Patients. A Multicenter, Phase II, Sham-Controlled, Randomized Trial: The PROPEL Study.
Heyland, DK, Marquis, F, Lamontagne, F, Albert, M, Turgeon, AF, Khwaja, KA, Garland, A, Hall, R, Chapman, MG, Kutsiogannis, DJ, et al
Critical care medicine. 2020;(3):e219-e226
Abstract
OBJECTIVES To evaluate the effect of esophageal stimulation on nutritional adequacy in critically ill patients at risk for enteral feeding intolerance. DESIGN A multicenter randomized sham-controlled clinical trial. SETTING Twelve ICUs in Canada. PATIENTS We included mechanically ventilated ICU patients who were given moderate-to-high doses of opioids and expected to remain alive and ventilated for an additional 48 hours and who were receiving enteral nutrition or expected to start imminently. INTERVENTIONS Patients were randomly assigned 1:1 to esophageal stimulation via an esophageal stimulating catheter (E-Motion Tube; E-Motion Medical, Tel Aviv, Israel) or sham treatment. All patients were fed via these catheters using a standardized feeding protocol. MEASUREMENTS AND MAIN RESULTS The co-primary outcomes were proportion of caloric and protein prescription received enterally over the initial 7 days following randomization. Among 159 patients randomized, the modified intention-to-treat analysis included 155 patients: 73 patients in the active treatment group and 82 in the sham treatment group. Over the 7-day study period, the percent of prescribed caloric intake (± SE) received by the enteral route was 64% ± 2 in the active group and 65% ± 2 in sham patients for calories (difference, -1; 95% CI, -8 to 6; p = 0.74). For protein, it was 57% ± 3 in the active group and 60% ± 3 in the sham group (difference, -3; 95% CI, -10 to 3; p = 0.30). Compared to the sham group, there were more serious adverse events reported in the active treatment group (13 vs 6; p = 0.053). Clinically important arrhythmias were detected by Holter monitoring in 36 out of 70 (51%) in the active group versus 22 out of 76 (29%) in the sham group (p = 0.006). CONCLUSIONS Esophageal stimulation via a special feeding catheter did not improve nutritional adequacy and was associated with increase risk of harm in critically ill patients.
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Oropharyngeal Colostrum Positively Modulates the Inflammatory Response in Preterm Neonates.
Martín-Álvarez, E, Diaz-Castro, J, Peña-Caballero, M, Serrano-López, L, Moreno-Fernández, J, Sánchez-Martínez, B, Martín-Peregrina, F, Alonso-Moya, M, Maldonado-Lozano, J, Hurtado-Suazo, JA, et al
Nutrients. 2020;(2)
Abstract
During the first days of life, premature infants have physiological difficulties swallowing, thereby missing out on the benefits of breastfeeding. The aim of this study is to assess the effects of oropharyngeal mother's milk administration in the inflammatory signaling of extremely premature infants. Neonates (n = 100) (<32 week's gestation and/or <1500 g) were divided into two groups: mother's milk group (n = 48), receiving 0.2 mL of oropharyngeal mother's milk every 4 h for the first 15 days of life, and a control group (n = 52), not receiving oropharyngeal mother's milk. Serum concentrations of interleukin (IL) IL-6, IL-8, IL-10, IL-1ra, tumor necrosis factor alpha (TNF-α), and interferón gamma (IFN-γ) were assessed at 1, 3, 15, and 30 days of postnatal life. Maternal and neonatal outcomes were collected. The rate of common neonatal morbidities in both groups was similar. The mother's milk group achieved full enteral feeding earlier, and showed a decrease in Il-6 on days 15 and 30, in IL-8 on day 30, and in TNF-α and INF-γ on day 15, as well as an increase in IL-1ra on days 3 and 15 and in IL-10 on day 30. Oropharyngeal mother's milk administration for 15 days decreases the pro-inflammatory state of preterm neonates and provides full enteral nutrition earlier, which could have a positive influence on the development of the immune system and inflammatory response, thereby positively influencing other developmental outcomes.
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Individualising care in severe bronchopulmonary dysplasia: a series of N-of-1 trials comparing transpyloric and gastric feeding.
Jensen, EA, Zhang, H, Feng, R, Dysart, K, Nilan, K, Munson, DA, Kirpalani, H
Archives of disease in childhood. Fetal and neonatal edition. 2020;(4):399-404
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OBJECTIVE Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia. DESIGN N-of-1 multiple crossover trials with individual patient and pooled data analyses. SETTING Level IV intensive care nursery. PATIENTS Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016. INTERVENTION N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order. MAIN OUTCOME MEASURES The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO2 ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO2 ≤80% and mean daily fraction of inspired oxygen. RESULTS Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5). CONCLUSIONS Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants. TRIAL REGISTRATION NUMBER NCT02142621.
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Enteral Nutrition Support Does Not Improve PNI in Radiotherapy Patients with Locally Advanced Esophageal Cancer.
Ye, Y, Xu, Y, Fu, Q, Shen, P, Chen, Y, Zheng, P, Song, L, Chen, Y, Wang, J
Nutrition and cancer. 2019;(2):223-229
Abstract
OBJECTIVE The assessment of prognostic nutritional index (PNI) before and during radiotherapy is an important parameter for the prognosis in patients with cancer. In this study, enteral tube feeding (ETF) was used during radiotherapy in patients with EC. Dynamic changes of various nutritional indicators (including PNI) were monitored. METHODS Patients with EC who underwent radiotherapy between June 2016 and July 2017 were enrolled. ETF was performing with the energy of 25 kcal × kg/d. Nutritional status were evaluated. Least significant difference (LSD) was used for multiple comparisons between groups. RESULTS A total of 148 patients were admitted, including 51 patients fed via ETF. For patients who were not scheduled to nutritional support, significant difference were observed in albumin (ALB) (P < 0.001), prealbimnin (PA) (P = 0.05) and PNI (P < 0.001) compared to levels before radiotherapy. In the patients fed via enteral tube, no significant difference were found in weight, BMI, ALB, retinol binding protein (RBP) and PA before and after radiotherapy, while PNI significantly decreased (P < 0.001). CONCLUSION After preforming ETF with the energy of 25 kcal × kg/d in patients with EC during radiotherapy, PNI, the key nutritional index reflecting prognosis, significantly decreased.
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Comparison of tube feeding in stroke patients: Nasogastric tube feeding versus oroesophageal tube feeding-A pilot study.
Park, JW, Park, KD, Kim, TH, Lee, JY, Lim, OK, Lee, JK, Choi, C
Medicine. 2019;(30):e16472
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BACKGROUNDS Patients with central nervous system injuries present with dysphagia and may require non-oral feeding methods, like percutaneous endoscopic gastrostomy, nasogastric (NG) tube, or oroesophageal (OE) tube. The prevalence of pneumonia in patients with gastroesophageal reflux (GER) is significantly higher than that in patients without GER. We aimed to determine the most appropriate tube feeding with low risk of GER by comparing the results of 24-hour pH monitoring studies in patients who were administered 2 types of feeding: NG tube and OE tube. METHODS In this pilot study, 6 stroke patients underwent 24-hour esophageal pH monitoring during NG tube feeding and OE tube feeding, sequentially. Parameters collected included acid exposure time, mean esophageal pH, number of reflux episode, time of bolus reflux for both total 24-hour pH study data and postprandial data, and deMeester composite score. RESULTS Total acid reflux time (minutes) decreased more with OE tube feeding than that with NG tube feeding in the total 24-hour pH study. The number of reflux episodes decreased in both total and postprandial data with OE tube feeding versus NG tube feeding (P < .05). There were no significant differences in mean esophageal pH and total time of bolus reflux between the 2 groups. CONCLUSIONS Although we could not definitively conclude that OE tube feeding decreased the severity of GER compared with NG tube feeding, there were significant differences in 4 out of 9 parameters. OE tube can be a substitute for NG tube in patients with dysphagia after stroke leading to GER disease.
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Study protocol for the Augmented versus Routine Approach to Giving Energy Trial (TARGET).
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Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine. 2018;(1):6-14
Abstract
BACKGROUND Nutrition is routinely provided to critically ill patients who are mechanically ventilated and remain in the intensive care unit for more than a few days. Nasogastric feeding, which is standard practice for patients who are unable to tolerate oral nutrition, typically delivers less than 60% of the recommended energy requirements. It remains uncertain whether the delivery of about 100% of the recommended energy goals via the enteral route will affect survival and other important clinical outcomes. OBJECTIVE To describe the protocol for a large-scale, multicentre, double-blind, randomised, controlled, parallelgroup, phase 3 clinical trial to determine if augmentation of calorie delivery using an energy-dense enteral nutrition formulation in mechanically ventilated patients increases 90-day survival when compared with routine care. METHODS 4000 patients who are mechanically ventilated and are expected to receive enteral nutrition for more than 2 days are to be randomised to an energy-dense formulation (1.5 kcal/mL) or routine enteral feed formulation (1 kcal/mL), given at the same rate. The primary outcome is 90-day all-cause mortality. Secondary outcomes include cause-related mortality up to Day 90; all-cause mortality at hospital discharge and at Days 28 and 180 after randomisation; and ventilator-, vasopressorand renal replacement-free days to Day 28. Health-related quality of life and functional assessments will be conducted at Day 180 after randomisation. RESULTS AND CONCLUSIONS The results of this trial are expected to determine whether increased energy delivery, using an energy-dense formula can improve clinically meaningful outcomes, including survival.