Marianne J. Chapman

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.

Antro-pyloro-duodenal motor responses to gastric and duodenal nutrient in critically ill patients

Background: Gastric emptying is frequently delayed in critical illness which compromises the success of nasogastric nutrition. The underlying motor dysfunctions are poorly defined. Aims: To characterise antro-pyloro-duodenal motility during fasting, and in response to gastric and duodenal nutrient, as well as to evaluate the relationship between gastric emptying and motility, in the critically ill. Subjects: Fifteen mechanically ventilated patients from a mixed intensive care unit; 10 healthy volunteers. Methods: Antro-pyloro-duodenal pressures were recorded during fasting, after intragastric administration (100 ml; 100 kcal), and during small intestinal infusion of liquid nutrient (6 hours; 1 kcal/min). Gastric emptying was measured using a 13C octanoate breath test. Results: In healthy subjects, neither gastric nor small intestinal nutrient affected antro-pyloro-duodenal pressures. In patients, duodenal nutrient infusion reduced antral activity compared with both fasting and healthy subjects (0.03 (0–2.47) waves/min v 0.14 (0–2.2) fasting (p = 0.016); and v 0.33 (0–2.57)/min in healthy subjects (p = 0.005)). Basal pyloric pressure and the frequency of phasic pyloric pressure waves were increased in patients during duodenal nutrient infusion (3.12 (1.06) mm Hg; 0.98 (0.13)/min) compared with healthy subjects (−0.44 (1.25) mm Hg; p<0.02 after 120 minutes; 0.29 (0.15)/min; p = 0.0002) and with fasting (−0.06 (1.05) mm Hg; p<0.03 after 160 minutes; 0.49 (0.13)/min; (p = 0.0001). Gastric emptying was delayed in patients (gastric emptying coefficient 2.99 (0.2) v 3.47 (0.1); p = 0.015) and inversely related to the number of pyloric pressure waves (r = −0.563, p = 0.029). Conclusions: Stimulation of pyloric and suppression of antral pressures by duodenal nutrient are enhanced in the critically ill and related to decreased gastric emptying.

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.

IntroductionHyperglycaemia 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.MethodsSeven 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.ResultsIn 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).ConclusionsAcute, 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 RegistrationAustralian New Zealand Clinical Trials Registry number: ACTRN12609000093280.

Gastrointestinal motility and prokinetics in the critically ill.

Purpose of reviewEnteral nutrition is frequently unsuccessful in the critically ill due to gastrointestinal dysfunction. Current treatment strategies are often disappointing. In this article upper gastrointestinal function in health together with abnormalities seen during critical illness are reviewed, and potential therapeutic options summarized. Recent findingsReflux oesophagitis occurs frequently due to reduced or absent lower oesophageal sphincter tone. In the stomach a number of motor patterns contribute to slow gastric emptying. The fundus has reduced compliance, there are less frequent contractions in both the proximal and distal stomach, isolated pyloric activity is increased and the organization of duodenal motor activity is abnormal. In response to nutrients, enterogastric feedback is enhanced, fundic relaxation and subsequent recovery is delayed, antral motility is further reduced and localized pyloric contractions stimulated. Elevated concentrations of hormones such as cholecystokinin and peptide YY are potential mediators for these phenomena. Rapid tachyphylaxis occurs with the commonly used prokinetics, metoclopramide and erythromycin, and novel agents are under investigation. Independent of gastric emptying, nutrient absorption is reduced. SummaryThere has been considerable progress in understanding the pathogenesis of mechanisms causing feed intolerance in critical illness, but this is yet to be translated into therapeutic benefit.

Feed intolerance in critical illness is associated with increased basal and nutrient-stimulated plasma cholecystokinin concentrations

Objective: Delayed gastric emptying and intolerance to gastric feeding occur frequently in the critically ill. In these patients, gastric motor responses to nutrients are disturbed. Cholecystokinin (CCK) slows gastric emptying. The aim of this study was to determine plasma CCK concentrations during fasting and in response to small‐intestine nutrient infusion in critically ill patients. Design: Randomized, controlled trial. Setting: Level 3, mixed medical and surgical intensive care unit. Subjects: A total of 31 mechanically ventilated, critically ill patients (23 men, 51 ± 3 yrs) and 28 healthy subjects (21 men, 43 ± 2 yrs). Interventions: Subjects received two 60‐min duodenal infusions of Ensure (complete balanced nutrition), at 1 and 2 kcal/min, in a randomized, single‐blind fashion. The nutrient infusions were separated by a 2‐hr “washout” period. Blood samples for measurement of plasma CCK concentrations were obtained immediately before and every 20 mins during nutrient infusion. Measurements and Main Results: Baseline and nutrient‐stimulated plasma CCK concentrations were higher in critically ill patients compared with healthy subjects (p < .001). The magnitude of the rise in plasma CCK in response to nutrients was also greater in the critically ill (p < .01). Of the 23 patients who received enteral nutrition before the study, nine were intolerant of gastric feeding. In these patients, both the baseline plasma CCK concentration and the magnitude of CCK increase during nutrient infusions were greater than in patients with feed tolerance (p < .002). Impaired renal function was associated with an increased baseline CCK concentration but had no effect on the CCK response to nutrients. Conclusions: Both fasting and nutrient‐stimulated plasma CCK concentrations are increased in critically ill patients, particularly in those with feed intolerance. This may provide a humoral mechanism for delayed gastric emptying seen in critical illness.

Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: Relationship to glycemia

Objective:To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients. Design:Randomized, double-blind, crossover study. Setting:Intensive care unit. Subjects:Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days. Interventions:Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between −30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 &mgr;g of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered. Measurements and Main Results:Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve0–330, 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, −15 [15] vs. −3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve−30–330, 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve0–330, 2071 [353] vs. 2419 [594] mmol/L/min; p = .001). Conclusions:Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.