Sucrose malabsorption and impaired mucosal integrity in enterally fed critically ill patients: a prospective cohort observational study.

OBJECTIVE: Inadequate nutrition is common in critical illness due in part to gastric stasis. However, recent data suggest that altered small intestinal mucosal function may be a contributing factor. The aim of this study was to examine the effects of critical illness on sucrose absorption, permeability, and mucosal morphology. DESIGN: Prospective, observational study. SETTING: Tertiary critical care unit. SUBJECTS: Twenty mechanically ventilated patients (19 men; 52.2 ± 20.5 yr; 9 feed intolerant; Acute Physiology and Chronic Health Evaluation II score 16.2 ± 6.0) and 20 healthy subjects (14 men; 51.6 ± 21.5 yr). INTERVENTIONS: Following a 4-hr fast, a "meal" (100 kcal Ensure, 20-g enriched C-sucrose, 1.1 g rhamnose, 7.5 mL lactulose) was administered into the small intestine. Sucrose absorption was evaluated by analyzing 13CO2 concentration (cumulative percent of administered 13C dose recovered) in expiratory breath samples taken at timed intervals. At 90 minutes, a plasma lactulose/rhamnose concentration was also measured, with lactulose/rhamnose ratio, a marker of small intestinal mucosal permeability. When possible duodenal biopsies were taken in critically ill patients on insertion of the small intestinal feeding catheter and examined for disaccharidase levels and histology. Data are mean ± SD. RESULTS: When compared with healthy subjects, critically ill patients had significantly reduced cumulative CO2 recovery (90 min: 1.78% ± 1.98% vs. 8.04% ± 2.55%; p < 0.001) and increased lactulose/rhamnose ratio (2.77 ± 4.24 vs.1.10 ± 0.98; p = 0.03). The lactulose/rhamnose ratio was greater in feed-intolerant patients (4.06 ± 5.38; p = 0.003). In five patients, duodenal mucosal biopsy showed mild to moderate epithelial injury. Sucrase levels were normal in all patients. CONCLUSIONS: Sucrose absorption is reduced and intestinal permeability increased in critically ill patients, possibly indicating an impairment of small intestinal mucosal function. These results, however, are discordant with duodenal mucosal histology and sucrase levels. This may reflect an inactivation of sucrase in vivo or inadequate nutrient exposure to the brush border due to small intestinal dysmotility.

Delayed enteral feeding impairs intestinal carbohydrate absorption in critically ill patients.

OBJECTIVES: Delay in initiating enteral nutrition has been reported to disrupt intestinal mucosal integrity in animals and to prolong the duration of mechanical ventilation in humans. However, its impact on intestinal absorptive function in critically ill patients is unknown. The aim of this study was to examine the impact of delayed enteral nutrition on small intestinal absorption of 3-O-methyl-glucose. DESIGN: Prospective, randomized study. SETTING: Tertiary critical care unit. PATIENTS: Studies were performed in 28 critically ill patients. INTERVENTIONS: Patients were randomized to either enteral nutrition within 24 hrs of admission (14 "early feeding": 8 males, 6 females, age 54.9 ± 3.3 yrs) or no enteral nutrition during the first 4 days of admission (14 "delayed feeding": 10 males, 4 females, age 56.1 ± 4.2 yrs). MEASUREMENTS AND MAIN RESULTS: Gastric emptying (scintigraphy, 100 mL of Ensure (Abbott Australia, Kurnell, Australia) with 20 MBq Tc-suphur colloid), intestinal absorption of glucose (3 g of 3-O-methyl-glucose), and clinical outcomes were assessed 4 days after intensive care unit admission. Although there was no difference in gastric emptying, plasma 3-O-methyl-glucose concentrations were less in the patients with delayed feeding compared to those who were fed earlier (peak: 0.24 ± 0.04 mmol/L vs. 0.37 ± 0.04 mmol/L, p < .02) and integrated (area under the curve at 240 mins: 38.5 ± 7.0 mmol/min/L vs. 63.4 ± 8.3 mmol/min/L, p < .04). There was an inverse correlation between integrated plasma concentrations of 3-O-methyl-glucose (area under the curve at 240 mins) and the duration of ventilation (r = -.51; p = .006). In the delayed feeding group, both the duration of mechanical ventilation (13.7 ± 1.9 days vs. 9.2 ± 0.9 days; p = .049) and length of stay in the intensive care unit (15.9 ± 1.9 days vs. 11.3 ± 0.8 days; p = .048) were greater. CONCLUSIONS: In critical illness, delaying enteral feeding is associated with a reduction in small intestinal glucose absorption, consistent with the reduction in mucosal integrity after nutrient deprivation evident in animal models. The duration of both mechanical ventilation and length of stay in the intensive care unit are prolonged. These observations support recommendations for "early" enteral nutrition in critically ill patients.

The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study.

INTRODUCTION: Hyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia. METHODS: Seven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured. RESULTS: In all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30-270 min GLP-1 (2077 +/- 144 mmol/l min) vs placebo (2568 +/- 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 +/- 0.7 mmol/l) vs placebo (12.7 +/- 1.0 mmol/l); P < 0.01). The insulin/glucose ratio at 270 minutes was increased with GLP-1 infusion (GLP-1 (9.1 +/- 2.7) vs. placebo (5.8 +/- 1.8); P = 0.02) but there was no difference in absolute insulin concentrations. There was a transient, non-sustained, reduction in plasma glucagon concentrations during GLP-1 infusion (t = 30 minutes GLP-1 (90 +/- 12 pmol/ml) vs. placebo (104 +/- 10 pmol/ml); P < 0.01). CONCLUSIONS: Acute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number: ACTRN12609000093280.

Glucose absorption and gastric emptying in critical illness.

INTRODUCTION: Delayed gastric emptying occurs frequently in critically ill patients and has the potential to adversely affect both the rate, and extent, of nutrient absorption. However, there is limited information about nutrient absorption in the critically ill, and the relationship between gastric emptying (GE) and absorption has hitherto not been evaluated. The aim of this study was to quantify glucose absorption and the relationships between GE, glucose absorption and glycaemia in critically ill patients. METHODS: Studies were performed in nineteen mechanically-ventilated critically ill patients and compared to nineteen healthy subjects. Following 4 hours fasting, 100 ml of Ensure, 2 g 3-O-methyl glucose (3-OMG) and 99mTc sulphur colloid were infused into the stomach over 5 minutes. Glucose absorption (plasma 3-OMG), blood glucose levels and GE (scintigraphy) were measured over four hours. Data are mean +/- SEM. A P-value < 0.05 was considered significant. RESULTS: Absorption of 3-OMG was markedly reduced in patients (AUC240: 26.2 +/- 18.4 vs. 66.6 +/- 16.8; P < 0.001; peak: 0.17 +/- 0.12 vs. 0.37 +/- 0.098 mMol/l; P < 0.001; time to peak; 151 +/- 84 vs. 89 +/- 33 minutes; P = 0.007); and both the baseline (8.0 +/- 2.1 vs. 5.6 +/- 0.23 mMol/l; P < 0.001) and peak (10.0 +/- 2.2 vs. 7.7 +/- 0.2 mMol/l; P < 0.001) blood glucose levels were higher in patients; compared to healthy subjects. In patients; 3-OMG absorption was directly related to GE (AUC240; r = -0.77 to -0.87; P < 0.001; peak concentrations; r = -0.75 to -0.81; P = 0.001; time to peak; r = 0.89-0.94; P < 0.001); but when GE was normal (percent retention240 < 10%; n = 9) absorption was still impaired. GE was inversely related to baseline blood glucose, such that elevated levels were associated with slower GE (ret 60, 180 and 240 minutes: r > 0.51; P < 0.05). CONCLUSIONS: In critically ill patients; (i) the rate and extent of glucose absorption are markedly reduced; (ii) GE is a major determinant of the rate of absorption, but does not fully account for the extent of impaired absorption; (iii) blood glucose concentration could be one of a number of factors affecting GE.

Age-related impairment of esophagogastric junction relaxation and bolus flow time.

AIM: To investigate the functional effects of abnormal esophagogastric (EGJ) measurements in asymptomatic healthy volunteers over eighty years of age. METHODS: Data from 30 young controls (11 M, mean age 37 ± 11 years) and 15 aged subjects (9 M, 85 ± 4 years) were compared for novel metrics of EGJ-function: EGJ-contractile integral (EGJ-CI), "total" EGJ-CI and bolus flow time (BFT). Data were acquired using a 3.2 mm, 25 pressure (1 cm spacing) and 12 impedance segment (2 cm) solid-state catheter (Unisensor and MMS Solar GI system) across the EGJ. Five swallows each of 5 mL liquid (L) and viscous (V) bolus were analyzed. Mean values were compared using Student's t test for normally distributed data or Mann Whitney U-test when non-normally distributed. A P value < 0.05 was considered significant. RESULTS: EGJ-CI at rest was similar for older subjects compared to controls. "Total" EGJ-CI, measured during liquid swallowing, was increased in older individuals when compared to young controls (O 39 ± 7 mmHg.cm vs C 18 ± 3 mmHg.cm; P = 0.006). For both liquid and viscous bolus consistencies, IRP4 was increased (L: 11.9 ± 2.3 mmHg vs 5.9 ± 1.0 mmHg, P = 0.019 and V: 14.3 ± 2.4 mmHg vs 7.3 ± 0.8 mmHg; P = 0.02) and BFT was reduced (L: 1.7 ± 0.3 s vs 3.8 ± 0.2 s and V: 1.9 ± 0.3 s vs 3.8 ± 0.2 s; P < 0.001 for both) in older subjects, when compared to young. A matrix of bolus flow and presence above the EGJ indicated reductions in bolus flow at the EGJ occurred due to both impaired bolus transport through the esophageal body (i.e., the bolus never reached the EGJ) and increased flow resistance at the EGJ (i.e., the bolus retained just above the EGJ). CONCLUSION: Bolus flow through the EGJ is reduced in asymptomatic older individuals. Both ineffective esophageal bolus transport and increased EGJ resistance contribute to impaired bolus flow.

Changes in esophageal and lower esophageal sphincter motility with healthy aging.

BACKGROUND AND AIMS: Swallowing difficulties become increasingly prevalent in older age. Differences exist in lower esophageal sphincter (LES) function between older and younger patients with dysphagia, but the contribution of aging per se to these is unclear. METHODS: Esophageal motor function was measured using high resolution manometry in older (aged 81+/-1.7 yrs) and younger (23+/-1.7 yrs) asymptomatic healthy adults. After baseline recording, motility was assessed by swallowing boluses of liquid (right lateral and upright postures) and solids. Basal LES pressure, integrated relaxation pressure, distal esophageal peristaltic amplitude, distal contractile integral and velocity were measured. Data are presented as mean +/- SEM. RESULTS: Despite a trend for lower basal LES pressure (15.8+/-2.9 mmHg vs. 21.0+/-0.2 mmHg; P=0.08), completeness of LES relaxation was reduced in older subjects (liquid RL: P=0.003; UR: P=0.007; solid: P=0.03), with higher integrated relaxation pressure when upright (liquid: 6.9+/-1.1 vs. 3.1+/-0.4 mmHg; P=0.01; solids: 8.1+/-1.1 vs. 3.6+/-0.3 mmHg; P=0.001) and a longer time to recovery after liquid boluses (right lateral: P=0.01; upright: P=0.04). In young, but not older adults, esophageal peristaltic velocity was increased when upright (3.6+/-0.2 cm/sec; P=0.04) and reduced with solids (3.0+/-0.1 cm-s; P=0.03). Distal contraction amplitude was higher with solid cf. liquid in the younger individuals (51.8+/-7.9 mmHg vs. 41.4+/-6.2 mmHg; P=0.03). In elderly subjects, the distal contractile integral was higher with liquid swallows in the upright posture (P=0.006). CONCLUSION: There are subtle changes in LES function even in asymptomatic older individuals. These age-related changes may contribute to the development of dysphagia.

Modulation of individual components of gastric motor response to duodenal glucose.

AIM: To evaluate individual components of the antro-pyloro-duodenal (APD) motor response to graded small intestinal glucose infusions in healthy humans. METHODS: APD manometry was performed in 15 healthy subjects (12 male; 40 ± 5 years, body mass index 26.5 ± 1.6 kg/m(2)) during four 20-min intraduodenal infusions of glucose at 0, 0.5, 1.0 and 1.5 kcal/min, in a randomised double-blinded fashion. Glucose solutions were infused at a rate of 1 mL/min and separated by 40-min "wash-out" period. Data are mean ± SE. Inferential analyses are repeated measure analysis of variance with Bonferroni post-hoc testing. RESULTS: At 0 kcal/min frequency of pressure waves were: antrum (7.5 ± 1.8 waves/20 min) and isolated pyloric pressure waves (IPPWs) (8.0 ± 2.3 waves/20 min) with pyloric tone (0.0 ± 0.9 mmHg). Intraduodenal glucose infusion acutely increased IPPW frequency (P < 0.001) and pyloric tone (P = 0.015), and decreased antral wave frequency (P = 0.007) in a dose-dependent fashion. A threshold for stimulation was observed at 1.0 kcal/min for pyloric phasic pressure waves (P = 0.002) and 1.5 kcal/min for pyloric tone and antral contractility. CONCLUSION: There is hierarchy for the activation of gastrointestinal motor responses to duodenal glucose infusion. An increase in IPPWs is the first response observed.

Lower esophageal sphincter relaxation is impaired in older patients with dysphagia.

AIM: To characterize the effects of age on the mechanisms underlying the common condition of esophageal dysphagia in older patients, using detailed manometric analysis. METHODS: A retrospective case-control audit was performed on 19 patients aged ≥ 80 years (mean age 85 ± 0.7 year) who underwent a manometric study for dysphagia (2004-2009). Data were compared with 19 younger dysphagic patients (32 ± 1.7 years). Detailed manometric analysis performed prospectively included basal lower esophageal sphincter pressure (BLESP), pre-swallow and nadir LESP, esophageal body pressures and peristaltic duration, during water swallows (5 mL) in right lateral (RL) and upright (UR) postures and with solids. Data are mean ± SE; a P-value < 0.05 was considered significant. RESULTS: Elderly dysphagic patients had higher BLESP than younger patients (23.4 ± 3.8 vs 14.9 ± 1.2 mmHg; P < 0.05). Pre-swallow LESP was elevated in the elderly in both postures (RL: 1 and 4 s P = 0.019 and P = 0.05; UR: P < 0.05 and P = 0.05) and solids (P < 0.01). In older patients, LES nadir pressure was higher with liquids (RL: 2.3 ± 0.6 mmHg vs 0.7 ± 0.6 mmHg, P < 0.05; UR: 3.5 ± 0.9 mmHg vs 1.6 ± 0.5 mmHg, P = 0.01) with shorter relaxation after solids (7.9 ± 1.5 s vs 9.7 ± 0.4 s, P = 0.05). No age-related differences were seen in esophageal body pressures or peristalsis duration. CONCLUSION: Basal LES pressure is elevated and swallow-induced relaxation impaired in elderly dysphagic patients. Its contribution to dysphagia and the effects of healthy ageing require further investigation.

Relationship between altered small intestinal motility and absorption after abdominal aortic aneurysm repair.

PURPOSE: Small intestinal (SI) motor patterns are often disrupted after major non-gastrointestinal (non-GI) surgery, but the impact on luminal flow and nutrient absorption is unclear. This study examines interactions between SI motility, flow and absorption in the first 3 days after surgical repair of abdominal aortic aneurysm (AAA). METHODS: Concurrent assessments of SI motility (manometry), flow (impedancometry) and lipid (¹³C-triolein) and glucose [plasma 3-O-methyl-glucose (3-OMG)] absorption were performed in 13 patients (12 male; 77 ± 2 years) on days 1 and 3 post surgery during 3-h intra-duodenal nutrient infusion (Ensure® with 200 µl ¹³C-triolein, 3 g 3-OMG). Data, presented as mean ± standard error of mean (SEM), are compared with 10 healthy volunteers (9 male; 57 ± 4 years). RESULTS: On day 1 post surgery, there were more motility bursts, fewer impedance events and reduced absorption of ¹³C-triolein [cumulative percent dose recovery (cPDR) 22.9 ± 2.4% versus 31.2 ± 4.2%; P < 0.001] and 3-OMG, compared with health. By day 3, total number of bursts and flow events were similar between groups, with fewer retrograde and more antegrade flow episodes. ¹³C-triolein absorption remained low in patients on day 3 (26.7 ± 2.2%, P < 0.05), correlating positively with total number of flow events (r = 0.49; P < 0.01), but negatively with prolonged events (r = -0.37; P = 0.03). In patients, 3-OMG absorption increased from day 1 to 3 to a level comparable to health. CONCLUSIONS: Whilst disruption in SI motility and flow (impedance) events was associated with reduced absorption of both lipid and carbohydrate, lipid malabsorption was more prolonged. This may reflect inadequate mixing of chyme from altered motility, so varying the nutrient composition of enteral feed may improve absorption in these patients.

Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia.

INTRODUCTION: The role of glucagon-like peptide-1 (GLP-1) in the regulation of gastric emptying is uncertain. The aim of this study was to determine the effects of endogenous GLP-1 on gastric emptying, glucose absorption, and glycemia in health. METHODS: Ten healthy fasted subjects (eight males, two females; 48 +/- 7 yr) received the specific GLP-1 antagonist, exendin(9-39) amide [ex(9-39)NH(2)] (300 pmol/kg x min iv), or placebo, between -30 and 180 min in a randomized, double-blind, crossover fashion. At 0 min, a mashed potato meal ( approximately 2600 kJ) containing 3 g 3-ortho-methyl-D-glucose (3-OMG) and labeled with 20 MBq (99m)Technetium-sulphur colloid was eaten. Gastric emptying, including the time taken for 50% of the meal to empty from the stomach (T50), blood glucose, plasma 3-OMG, and plasma insulin were measured. RESULTS: Ex(9-39)NH(2) accelerated gastric emptying [T50 ex(9-39)NH(2), 68 +/- 8 min, vs. placebo, 83 +/- 7 min; P < 0.001] and increased the overall glycemic response to the meal [area under the curve (0-180 min) ex(9-39)NH(2), 1540 +/- 106 mmol/liter x min, vs. placebo, 1388 +/- 90 mmol/liter x min; P < 0.02]. At 60 min, ex(9-39)NH(2) increased the rise in glycemia [ex(9-39)NH(2), 9.9 +/- 0.5 mmol/liter, vs. placebo, 8.4 +/- 0.5 mmol/liter; P < 0.01], plasma 3-OMG [ex(9-39)NH(2), 0.25 +/- 0.01 mmol/liter, vs. placebo, 0.21 +/- 0.01 mmol/liter; P < 0.05], and plasma insulin [ex(9-39)NH(2), 82 +/- 13 mU/liter, vs. placebo, 59 +/- 9 mU/liter; P < 0.05] concentrations. There was a close within-subject correlation between glycemia and gastric emptying [e.g. at 60 min, the increment in blood glucose and gastric emptying (T50); r = -0.89; P < 0.001]. CONCLUSION: GLP-1 plays a physiological role to slow gastric emptying in health, which impacts on glucose absorption and, hence, postprandial glycemia.