Robert J. Fraser

Hyperglycaemia slows gastric emptying in Type 1 (insulin-dependent) diabetes mellitus

SummaryIn 10 patients with Type 1 (insulin-dependent) diabetes mellitus gastric emptying of a digestible solid and liquid meal was measured during euglycaemia (blood glucose concentration 4–8 mmol/l) and during hyperglycaemia (blood glucose concentration 16–20 mmol/l). Gastric emptying was studied with a scintigraphic technique and blood glucose concentrations were stabilised using a modified glucose clamp. Patients were also evaluated for gastrointestinal symptoms, autonomic nerve function and glycaemic control. When compared to euglycaemia, the duration of the lag phase before any of the solid meal emptied from the stomach (p = 0.032), the percentage of the solid meal remaining in the stomach at 100 min (p = 0.032) and the 50% emptying time for the solid meal (p = 0.032) increased during hyperglycaemia. The 50% emptying time for the liquid meal (p = 0.042) was also prolonged during the period of hyperglycaemia. These results demonstrate that the rate of gastric emptying in Type 1 diabetes is affected by the blood glucose concentration.

Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole.

To test the hypothesis that Helicobacter pylori infection is associated with a decreased intragastric acidity during omeprazole therapy, ambulatory 24 hour dual point gastric pH recordings were performed in 18 H pylori positive and 14 H pylori negative subjects. There was a four to six week washout period between the two pH recordings made in each subject after one week courses of placebo or omeprazole, 20 mg daily. During placebo, median 24 hour pH values were not different in the corpus (H pylori positive = 1.5, negative = 1.4; p = 0.9) or antrum (H pylori positive = 1.3, negative = 1.2; p = 0.1). However, during omeprazole treatment, median 24 hour pH values were higher in H pylori positive subjects, both in the corpus (H pylori positive = 5.5, negative = 4.0; p = 0.001) and antrum (H pylori positive = 5.5, negative = 3.5; p = 0.0004). During placebo treatment, the only difference between the two groups was a higher later nocturnal pH in the antrum in the H pylori positive group. During omeprazole treatment, gastric pH was higher both in the corpus and in the antrum in the H pylori positive group for all periods, except for mealtime in the corpus. These data indicate that omeprazole produces a greater decrease in gastric acidity in subjects with H pylori infection than in those who are H pylori negative. It is not, however, known whether there is a causal relationship between H pylori infection and increased omeprazole efficacy.

Disordered gastric motor function in diabetes mellitus.

SummaryThe application of novel investigative techniques has demonstrated that disordered gastric motility occurs frequently in diabetes mellitus. Gastric emptying is abnormal in about 50% of diabetic patients and delay in gastric emptying of nutrient-containing meals is more common than rapid emptying. The blood glucose concentration influences gastric motility in diabetes. In IDDM patients, gastric emptying is retarded during hyperglycaemia and may be accelerated by hypoglycaemia. Gastroparesis therefore does not necessarily reflect irreversible autonomic neuropathy and blood glucose concentrations must be monitored when gastric motility is evaluated in diabetic patients. There is a poor relationship between gastric emptying and gastrointestinal symptoms and the mechanisms by which abnormal motility causes symptoms are unclear. The introduction of new gastrokinetic drugs has improved therapeutic options for the management of symptomatic patients with gastroparesis considerably. The contribution of disordered gastric emptying to poor glycaemic control is unclear, but the demonstration that the rate of gastric emptying is a major factor in normal blood glucose homeostasis suggests that this is likely to be significant.

Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding

Objective To evaluate the effect of intravenous erythromycin on gastric emptying and the success of enteral feeding in mechanically ventilated, critically ill patients with large volume gastric aspirates. Design Prospective, double-blind, randomized, and placebo-controlled trial. Setting General intensive care unit in a university hospital. Patients Twenty critically ill, mechanically ventilated patients intolerant of nasogastric feeding (indicated by a residual gastric volume of ≥250 mL during feed administration at ≥40 mL/hr). Interventions After a gastric aspirate of ≥250 mL, which was discarded, the enteral feeding was continued at the previous rate for 3 hrs. Intravenous erythromycin (200 mg) or placebo was then administered over 20 mins. The residual gastric contents were again aspirated and the volume was recorded 1 hr after the infusion began. Measurements and Main Results Gastric emptying was calculated as volume of feed infused into the stomach over 4 hrs minus the residual volume aspirated. Mean gastric emptying was 139 ± 37 (±sem) mL after erythromycin and −2 ± 46 mL after placebo (p = .027). Nasogastric feeding was successful in nine of ten patients treated with erythromycin and five of ten who received placebo 1 hr after infusion (chi-square p = .05). Conclusion In critically ill patients who have large volumes of gastric aspirates indicating a failure to tolerate nasogastric feeding, a single small dose of intravenous erythromycin allows continuation of feed in the short term.

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.

Erythromycin is more effective than metoclopramide in the treatment of feed intolerance in critical illness.

Objective:This study aimed to a) compare the efficacy of metoclopramide and erythromycin in the treatment of feed intolerance in critical illness; and b) determine the effectiveness of “rescue” combination therapy in patients who fail monotherapy. Design:Randomized controlled trial. Setting:Level III mixed medical and surgical intensive care unit. Patients:Ninety mechanically ventilated, medical patients with feed-intolerance (gastric residual volume ≥250 mL). Interventions:Patients received either metoclopramide 10 mg intravenously four times daily (n = 45) or erythromycin 200 mg intravenously twice a day (n = 45) in a double-blind, randomized fashion. After the first dose, nasogastric feeding was commenced and 6-hourly nasogastric aspirates were performed. If a gastric residual volume ≥250 mL recurred on treatment, open-label, combination therapy was given. Patients were studied for 7 days. Successful feeding was defined as 6-hourly gastric residual volume <250 mL with a feeding rate ≥40 mL/hr. Measurements and Main Results:Demographic data, blood glucose levels, and use of inotropes, opioids, and benzodiazepines were similar between the two groups. After 24 hrs of treatment, both monotherapies reduced the mean gastric residual volume (metoclopramide, 830 ± 32 mL to 435 ± 30 mL, p < .0001; erythromycin, 798 ± 33 mL to 201 ± 19 mL, p < .0001) and improved the proportion of patients with successful feeding (metoclopramide = 62% and erythromycin = 87%). Treatment with erythromycin was more effective than metoclopramide, but the effectiveness of both treatments declined rapidly over time. In patients who failed monotherapy, rescue combination therapy was highly effective (day 1 = 92%) and maintained its effectiveness for the study duration (day 6 = 67%). High pretreatment gastric residual volume was associated with poor response to prokinetic therapy. Conclusions:In critical illness, erythromycin is more effective than metoclopramide in treating feed intolerance, but the rapid decline in effectiveness renders both treatments suboptimal. Rescue combination therapy is highly effective, and further study is required to examine its role as the first-line therapy.

Delayed gastric emptying in ventilated critically ill patients: Measurement by 13C-octanoic acid breath test

ObjectiveTo measure gastric emptying in ventilated critically ill patients with a new noninvasive breath test. DesignSingle-center, open study. SettingCombined medical and surgical intensive care unit of a university hospital. SubjectsThirty unselected mechanically ventilated critically ill patients receiving gastric feeding and 22 healthy volunteers. InterventionsNone. PatientsAfter 4 hrs without feeding, intragastric infusion of 100 mL of a liquid meal (Ensure) labeled with 100 &mgr;L 13C-octanoic acid. End-expiratory breath samples were collected into evacuated tubes from the respirator circuit every 5 mins for the first hour, then every 15 mins for 3 hrs. End-expiratory breath samples were also collected from volunteers studied supine after an overnight fast following an identical infusion via a nasogastric tube. Breath 13CO2 was measured with an isotope ratio mass spectrometer. Measurements and Main Results Performance of the breath test posed no difficulty or interference with patient care. The CO2 level was >1% in 1297/1300 breath samples, indicating satisfactory end-expiratory timing. Data are median and interquartile range. Gastric emptying was slower in patients compared with volunteers: gastric emptying coefficient 2.93 (2.17–3.39) vs. 3.58 (3.18–3.79), p < .001 and gastric half emptying time, derived from the area under the 13CO2 curve, 155 min (130–220) vs. 133 min (120–145), p < .008. Fourteen of the 30 patients had a gastric emptying coefficient <95% of all volunteers and 11 had a gastric half emptying time longer than 95% of all volunteers. The Acute Physiology and Chronic Health Evaluation (APACHE II) score (median 22, range 13–43) either at admission or on the day of the study did not correlate with gastric emptying coefficient. ConclusionGastric emptying of a calorie-dense liquid meal is slow in 40% to 45% of unselected mechanically ventilated patients in a combined medical and surgical intensive care unit. The 13C-octanoic acid breath test is a novel and useful bedside technique to measure gastric emptying in these patients.

Prokinetic therapy for feed intolerance in critical illness: one drug or two?

Objective:To compare the efficacy of combination therapy, with erythromycin and metoclopramide, to erythromycin alone in the treatment of feed intolerance in critically ill patients. Design:Randomized, controlled, double-blind trial. Setting:Mixed medical and surgical intensive care unit. Patients:Seventy-five mechanically ventilated, medical patients with feed intolerance (gastric residual volume ≥250 mL). Interventions:Patients received either combination therapy (n = 37; 200 mg of intravenous erythromycin twice daily + 10 mg of intravenous metoclopramide four times daily) or erythromycin alone (n = 38; 200 mg of intravenous erythromycin twice daily) in a prospective, randomized fashion. Gastric feeding was re-commenced and 6-hourly gastric aspirates performed. Patients were studied for 7 days. Successful feeding was defined as a gastric residual volume <250 mL with the feeding rate ≥40 mL/hr, over 7 days. Secondary outcomes included daily caloric intake, vomiting, postpyloric feeding, length of stay, and mortality. Measurements and Main Results:Demographic data; use of inotropes, opioids, or benzodiazepines; and pretreatment gastric residual volume were similar between the two groups. The gastric residual volume was significantly lower after 24 hrs of treatment with combination therapy, compared with erythromycin alone (136 ± 23 mL vs. 293 ± 45 mL, p = .04). Over the 7 days, patients treated with combination therapy had greater feeding success, received more daily calories, and had a lower requirement for postpyloric feeding, compared with erythromycin alone. Tachyphylaxis occurred in both groups but was less with combination therapy. Sedation, higher pretreatment gastric residual volume, and hypoalbuminemia were significantly associated with a poor response. There was no difference in the length of hospital stay or mortality rate between the groups. Watery diarrhea was more common with combination therapy (20 of 37 vs. 10 of 38, p = .01) but was not associated with enteric infections, including Clostridium difficile. Conclusions:In critically ill patients with feed intolerance, combination therapy with erythromycin and metoclopramide is more effective than erythromycin alone in improving the delivery of nasogastric nutrition and should be considered as the first-line treatment.

Impacts and patterns of disturbed gastrointestinal function in critically ill patients

Disordered upper gastrointestinal tract motility occurs frequently in intensive care unit patients and often represents a substantial treatment challenge. In addition to specific complications such as pulmonary aspiration and diarrhea, abnormal gastrointestinal motility is a limiting factor for delivery and success of enteral nutrition. The pathophysiologies involved are incompletely understood because of the difficulties of making measurements of gastrointestinal function in critically ill patients. With the recent development of techniques that overcome some of these difficulties, the prospects are brighter for significant advances in this field.

Esophageal body and lower esophageal sphincter function in healthy premature infants

BACKGROUND & AIMS Gastroesophageal reflux is a common problem in premature infants. The aim of this study was to use a novel manometric technique to measure esophageal body and lower esophageal sphincter pressures in premature infants. METHODS Micromanometric feeding assemblies (OD, < or = 2 mm) incorporating 4-9 manometric channels were used in 49 studies of 27 premature neonates. Esophageal body motility was recorded at three sites for 20 minutes after feeding. Twenty attempts (one per minute) were made to stimulate swallowing via facial stimulation (Santmyer reflex). In 32 studies lower esophageal sphincter pressures were recorded (sleeve) for 15 minutes before and after feeding. RESULTS Peristaltic motor patterns were less common than non-peristaltic motor patterns (26.6% vs. 73.4%; P < 0.0001) that comprised 31.1% synchronous, 34.6% incomplete, and 6.3% retrograde pressure waves. Reflex swallowing was elicited more frequently in neonates older than 34 weeks postconceptional age than in younger infants (33.4% vs. 20.4%; P < 0.05). Mean lower esophageal sphincter pressure was 20.5 +/- 1.7 mm Hg before and 13.7 +/- 1.3 mm Hg after feeding (P < 0.0005). CONCLUSIONS Premature infants show nonperistaltic esophageal motility that may contribute to poor clearance of refluxed material. In contrast, the lower esophageal sphincter mechanisms seem well developed.