cholecystokinin and Critical-Illness

Gastrointestinal dysmotility and dysfunction underlie our difficulties in providing adequate nutrition by the enteral route to our critically ill patients.. Recent studies have quantified gastric emptying and nutrient absorption. Slow gastric emptying is common and probably mediated by cholecystokinin and reduced active ghrelin concentrations. The cause of impaired nutrient absorption is not yet fully understood but may be related to small intestinal blood flow and/or mucosal factors. The absorption of the different macronutrients may be affected in different ways both by critical illness and by therapies. A better understanding of this may optimize the design of nutrient formulations in the future. New treatment modalities for gastrointestinal dysfunction are being investigated and include small intestinal feeding, nonpharmacological options such as acupuncture, and drugs including novel motilin receptor agonists, and opioid antagonists.. We are gradually developing a better understanding of how the gut works during critical illness, which has implications for optimizing the delivery of nutrition and thereby improving nutritional and clinical outcomes.

Topics: Cholecystokinin; Critical Illness; Enteral Nutrition; Evidence-Based Medicine; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Diseases; Ghrelin; Humans; Intestine, Small; Motilin; Naltrexone; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties.

Topics: Animals; Blood Glucose; Cholecystokinin; Critical Illness; Endocrine System; Gastrointestinal Tract; Humans; Intestinal Absorption; Peptide YY; Point-of-Care Systems

Numerous hormones secreted by the gut, during both the fasted state and in response to a meal, influence gastrointestinal motor and/or sensory function, and appear to contribute to the pathogenesis of delayed gastric emptying associated with gastroparesis, functional dyspepsia (FD) and feed intolerance in critical illness. Gut hormones are, accordingly, potential targets for the management of these patients.. This article will discuss the hypersensitivity to enteral fat and endogenous (nutrient-stimulated) and exogenous cholecystokinin (CCK) in patients with FD, and the elevation in both fasting and postprandial CCK levels evident in this group. It will review the use of pharmacological agonists of motilin and ghrelin, which accelerate gastric emptying, in the management of gastroparesis and FD. The frequent finding of markedly delayed gastric emptying in the critically ill will be examined; this is associated with elevated plasma CCK and peptide YY in both the fasted and postprandial states, which may account for the increase in small intestinal nutrient inhibitory feedback on gastric motility in this group. The concepts that the rate of gastric emptying is a major determinant of postprandial glycemic excursions in diabetes, and that modulation of gastric emptying may improve glycemic control, will be addressed; in type 1 and insulin-treated type 2 diabetic patients, co-ordination of insulin administration with nutrient delivery and absorption should be optimized, while type 2 patients who are not on insulin are likely to respond to dietary and/or pharmacological interventions which slow gastric emptying.

Topics: Adipose Tissue; Blood Glucose; Cholecystokinin; Critical Illness; Diabetes Mellitus; Dyspepsia; Gastric Emptying; Gastroparesis; Ghrelin; Glucagon-Like Peptide 1; Humans; Insulin; Peptide YY; Postprandial Period

Studies consistently show that nasogastric nutrition delivers only about 60% of nutritional goals in critically ill patients. The predominant reason is abnormal gastric motility, leading to delayed gastric emptying, which is evident clinically as large gastric residual volumes. Delayed gastric emptying occurs in about 50%-60% of critically ill patients who are fed enterally and can result in malnutrition. Furthermore, delayed gastric emptying may increase the risk of aspiration of gastric contents. Recent research has improved our understanding of the complex abnormalities of gastric motor function that underlie delayed gastric emptying in the critically ill. Feed intolerance can be treated with prokinetic drugs and/or by the placement of postpyloric feeding catheters. The place of prokinetic agents in the treatment of feed intolerance is as yet unclear, but current evidence supports the administration of erythromycin combined with metoclopramide as first-line therapy. Other novel drugs, such as methylnaltrexone, mitemcinal, ghrelin agonists and dexloxiglumide, have potential advantages over these agents but require further investigation before widespread clinical use.

Topics: Antiemetics; Cholecystokinin; Critical Illness; Dopamine Antagonists; Drug Therapy, Combination; Enteral Nutrition; Erythromycin; Gastric Emptying; Gastrointestinal Agents; Ghrelin; Humans; Metoclopramide; Motilin; Receptors, Opioid, mu; Serotonin Receptor Agonists

Topics: Cholecystokinin; Critical Care; Critical Illness; Enteral Nutrition; Gastric Emptying; Humans

Enteral nutrient (EN) deprivation slows gastric emptying (GE) and increases plasma cholecystokinin (CCK) concentrations in healthy humans and may potentially contribute to the delayed GE in the critically ill. This study examined the impact of delayed feeding on GE, plasma CCK, and peptide YY (PYY) concentrations in the critically ill.. Randomized controlled trial.. Mixed medical and surgical intensive care unit (ICU).. Twenty-eight critically ill patients were randomized to receive EN either within 24 hrs of admission ("early feeding": 54.9 +/- 3.3 yrs; Acute Physiology and Chronic Health Evaluation (APACHE) II = 23.0 +/- 1.8) or on day 4 of admission after GE assessment ("delayed feeding": 56.1 +/- 4.2 yrs, APACHE II = 21.7 +/- 1.8). GE of 100 ml of Ensure was measured using scintigraphy on day 4 of admission. Blood was sampled for measurement of plasma CCK, PYY, and glucose concentrations.. Demographics, APACHE II score, use of inotrope and morphine sedation were similar between the groups. The mean administered/prescribed caloric ratio in the "early feeding" group was 72 +/- 4%. There were no differences in the retention of meal, intragastric meal distribution, proportion of patients with delayed GE (9/14 vs. 9/14), and plasma CCK and PYY concentrations during fasting and postprandially between the two groups. There was no relationship between the number of calories received and percentage of meal retention at 240 min (p > .05). However, delayed feeding was associated with longer duration of mechanical ventilations (13.7 +/- 1.9 vs. 9.2 +/- .9 days, p = .049) and length of stay in ICU (15.9 +/- 1.9 vs. 11.3 +/- 0.8 days, p = .048), but no difference in mortality.. In critical illness, delayed enteral feeding appears to have little impact on either GE or the enterogastric feedback hormones. However, the association between delayed feeding and increased duration of ventilation and length of stay in the ICU supports the current recommendation that enteral nutrition should be commenced early.

Topics: Cholecystokinin; Critical Illness; Enteral Nutrition; Female; Gastric Emptying; Humans; Male; Middle Aged; Peptide YY; Time Factors

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.. Randomized, controlled trial.. Level 3, mixed medical and surgical intensive care unit.. A total of 31 mechanically ventilated, critically ill patients (23 men, 51 +/- 3 yrs) and 28 healthy subjects (21 men, 43 +/- 2 yrs).. 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.. 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.. 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.

Topics: Adult; Analysis of Variance; APACHE; Cholecystokinin; Critical Illness; Dietary Sucrose; Duodenum; Enteral Nutrition; Fasting; Feedback, Physiological; Female; Food, Formulated; Gastric Emptying; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Intubation, Gastrointestinal; Kidney Diseases; Length of Stay; Male; Metabolic Clearance Rate; Respiration, Artificial; Single-Blind Method; Time Factors

The objective of this study was to gain insight into the hormonal responses to enteral nutrition in critically ill newborns requiring venoarterial extracorporeal membrane oxygenation (ECMO) by analyzing plasma gut hormone levels of gastrin, cholecystokinin and peptide-YY in relation to enteral nutrition.. In 24 consecutive neonates treated with venoarterial ECMO intestinal hormone secretions were determined by radioimmunoassay at 2-day intervals. Twelve received parenteral nutrition only. In 12 enteral nutrition was introduced later. The findings in these patients were compared with those of 16 measurements in eight non-ECMO treated age-matched controls. Mixed model analysis of variance was used for statistical analysis.. Concentrations of gastrin, cholecystokinin and peptide-YY were significantly higher in ECMO patients receiving enteral nutrition compared with ECMO patients who received parenteral nutrition (62, 3.8 and 59.4 pmol/L versus 46, 3.1 and 34.7 pmol/L, respectively). Overall, plasma hormone levels did not differ from those in age-matched controls.. Intestinal hormone levels showed normal responses after introduction of enteral feeding, comparable with those in age-matched controls without ECMO. These results do not provide an argument for withholding enteral nutrition even in the most severely ill neonates on venoarterial ECMO.

Topics: Analysis of Variance; Cholecystokinin; Critical Illness; Enteral Nutrition; Extracorporeal Membrane Oxygenation; Female; Gastrins; Humans; Infant, Newborn; Male; Parenteral Nutrition; Peptide YY; Radioimmunoassay; Treatment Outcome

Acetylcholine (Ach) is the key anti-inflammatory transmitter in the cholinergic anti-inflammatory pathway. In this study, critically ill patients treated with early enteral nutrition (EEN) were observed to explore whether EEN affected Ach levels and inflammation.. One hundred thirteen patients were included in this prospective observational study. All patients were provided the early enteral nutrition protocol 24-48 h after admission to the intensive care unit (ICU). Blood samples were collected, and the plasma levels of Ach, cholecystokinin (CCK), and inflammatory markers (tumour necrosis factor alpha (TNF-α), interleukin 1beta (IL1-β), and IL6) were measured on Days 0, 1, 3, 5, and 7. Nutritional intervention data were recorded within one week, including the number of patients receiving nutrition, the number of days nutrition was provided, the caloric intake and protein intake, feeding intolerance and prokinetic drug administration. Other collected data included the sequential organ failure assessment score (SOFA score), the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the use of mechanical ventilation (the number of patients and the duration), use of vasoactive drugs and the number of renal replacement treatments (RRT) received by each patient during their ICU stay. The primary outcome was 28-day mortality. Additionally, we analysed the correlation between plasma Ach levels and inflammation, as well as the correlation between plasma Ach and CCK levels. Moreover, a multivariate regression analysis was performed to examine the independent effects of different variables on 28-day mortality and Ach levels.. The overall 28-day mortality was 28.3% (32/113). Eighty-two patients tolerated enteral nutrition. Compared with Day 0 15.6 (2.8) nmol/l, the plasma Ach level was significantly increased on Day 3 18.6 (6.7) nmol/l, Day 5 19.3 (6.2) nmol/l and Day 7 19.7 (4.3) nmol/l (p < .001). Compared with Day 0176.2 (50.4) pg/ml, the plasma TNF-α level was significantly decreased on Day 3144.0 (77.4) pg/ml, Day 5127.3 (51.8) pg/ml and Day 7111.4 (42.5) pg/ml (p < .05). Compared with Day 0, the plasma IL1-β level was significantly decreased on Day 7 (p < .05). The plasma IL6 level was significantly decreased on Day 5 and Day 7 (p < .05) compared with Day 0. Compared with Day 0, the plasma CCK level was significantly increased on Day 3, 5 and 7 (p < .001). The correlation analysis revealed negative correlations between Ach levels and inflammation (p < .001), and a positive correlation between CCK and Ach levels (r = 0.775, p < .001). A comparison of patients who did or did not tolerate EEN revealed significant differences in the plasma levels of Ach, TNF-α, IL6 and CCK (p < .05). Significant differences in plasma levels of Ach, TNF-α, IL1-β, IL6 and CCK were observed between 28-day survivors and non-survivors (p < .05). The multivariate logistic regression analysis identified vasopressor support, RRT, the administration of EEN, SOFA score, APACHE II score at ICU admission and plasma Ach levels as independent determinants of 28-day mortality. Additionally, the multivariate linear regression analysis identified EEN, plasma lactate, mechanical ventilation, the SOFA score and plasma CCK levels as independent determinants of plasma Ach levels.. The administration of EEN to critically ill patients contributed to the increased plasma Ach levels and decreased inflammatory markers. The effect of EEN on Ach levels is partially attributed to the increase in CCK levels. Elevated plasma Ach levels indicate a better prognosis. Clinical trials identifier: NCT03612206.

Topics: Acetylcholine; Adult; Biomarkers; Cholecystokinin; Critical Illness; Energy Intake; Enteral Nutrition; Female; Humans; Inflammation; Intensive Care Units; Interleukin-1beta; Interleukin-6; Male; Middle Aged; Multiple Organ Failure; Nutritional Status; Organ Dysfunction Scores; Prognosis; Prospective Studies; Respiration, Artificial; Tumor Necrosis Factor-alpha

To quantify gallbladder dysfunction during critical illness.. Prospective observational comparison study of nutrient-stimulated gallbladder emptying in health and critical illness.. Single-centre mixed medical/surgical ICU.. Twenty-four mechanically ventilated critically ill patients suitable to receive enteral nutrition were compared with 12 healthy subjects.. Participants were studied after an 8-hour fast. Between 0 and 120 minutes, high-fat nutrient (20% intralipid) was infused via a postpyloric catheter into the duodenum at 2 kcal/min.. Three-dimensional images of the gallbladder were acquired at 30-minute intervals from -30 to 180 minutes. Ejection fraction (%) was calculated as changes between 0 and 120 minutes. Blood samples were obtained at 30-minute intervals for plasma cholecystokinin. Data are mean (SD) or median [interquartile range]. In the critically ill, fasting gallbladder volumes (critically ill, 61 mL [36-100 mL] vs healthy, 22 mL [15-25] mL; p < 0.001] and wall thickness (0.45 mm [0.15 mm] vs 0.26 mm [0.08 mm]; p < 0.001] were substantially greater, and sludge was evident in the majority of patients (71% vs 0%). Nutrient-stimulated emptying was incomplete in the critically ill after 120 minutes but was essentially complete in the healthy individuals (22 mL [9-66 mL] vs 4 mL [3-5 mL]; p < 0.01]. In five critically ill patients (21%), there was no change in gallbladder volume in response to nutrient, and overall ejection fraction was reduced in the critically ill (50% [8-83%] vs 77 [72-84%]; p = 0.01]. There were no differences in fasting or incremental cholecystokinin concentrations.. Fasted critically ill patients have larger, thicker-walled gallbladders than healthy subjects and nutrient-stimulated gallbladder emptying is impaired with "gallbladder paresis" occurring in approximately 20%.

Topics: Adult; Aged; Cholecystokinin; Critical Illness; Enteral Nutrition; Fasting; Female; Gallbladder Emptying; Humans; Imaging, Three-Dimensional; Male; Middle Aged; Prospective Studies; Ultrasonography

Altered concentrations of ghrelin, motilin, and cholecystokinin (CCK) may contribute to gastric hypomotility. The aims of this study were to evaluate the concentrations of these hormones in patients tolerant and intolerant to gastric nutrition, assess the influence of prokinetic therapy on these hormone concentrations, determine the associations between these mediators and gastric emptying, and evaluate whether inflammation influences their concentrations.. Post hoc analyses of 2 prospective studies that enrolled 20 critically ill patients with an aspirated gastric residual (GR) >150 mL while receiving gastric enteral nutrition (intolerant group) and 10 critically ill patients with minimal GR (tolerant group). Patients with intolerance were also assessed 1 day after prokinetic therapy. Fasting serum concentrations of total ghrelin, acyl ghrelin (active), des-acyl ghrelin (inactive), motilin, CCK, and tumor necrosis factor (TNF)-α were determined. Gastric emptying was assessed concurrently using the acetaminophen absorption method.. Compared to the tolerant group, the intolerant group had higher total ghrelin (1324.8 ± 1204.6 vs 285.1 ± 132.5 pg/mL; P < .001), lower acyl ghrelin (70.5 ± 65.4 vs 208.5 ± 186.9 pg/mL; P < .05), and lower acyl ghrelin to des-acyl ghrelin ratio (1.11 ± 1.35 vs 3.47 ± 3.21 pg/mL; P < .05). Concentrations of other hormones and TNF-α were similar. Despite accelerated gastric emptying after prokinetic therapy, concentrations of all hormones and TNF-α were similar to baseline values. Hormone concentrations were not associated with gastric emptying or TNF-α.. Patients intolerant to gastric nutrition generate less acyl ghrelin, which may contribute to gastric hypomotility. Intolerance is not associated with altered concentrations of other hormones. Hormone concentrations are not influenced by prokinetic therapy.

Topics: Adult; Aged; Cholecystokinin; Critical Illness; Enteral Nutrition; Female; Gastric Emptying; Gastrointestinal Hormones; Ghrelin; Humans; Inflammation; Male; Middle Aged; Motilin; Prospective Studies; Respiratory Aspiration; Stomach Diseases; Tumor Necrosis Factor-alpha

Topics: Cholecystokinin; Critical Illness; Gastric Emptying; Humans; Peptide YY; Time Factors

Cholecystokinin (CCK) and peptide YY (PYY) are released in response to intestinal nutrients and play an important physiological role in regulation of gastric emptying (GE). Plasma CCK and PYY concentrations are elevated in critically ill patients, particularly in those with a history of feed intolerance. This study aimed to evaluate the relationship between CCK and PYY concentrations and GE in critical illness.. GE of 100 mL of Ensure meal (106 kcal, 21% fat) was measured using a 13C-octanoate breath test in 39 mechanically ventilated, critically ill patients (24 males; 55.8 +/- 2.7 years old). Breath samples for 13CO2 levels were collected over the course of 4 hours, and the GE coefficient (GEC) (normal = 3.2 to 3.8) was calculated. Measurements of plasma CCK, PYY, and glucose concentrations were obtained immediately before and at 60 and 120 minutes after administration of Ensure.. GE was delayed in 64% (25/39) of the patients. Baseline plasma CCK (8.5 +/- 1.0 versus 6.1 +/- 0.4 pmol/L; P = 0.045) and PYY (22.8 +/- 2.2 versus 15.6 +/- 1.3 pmol/L; P = 0.03) concentrations were higher in patients with delayed GE and were inversely correlated with GEC (CCK: r = -0.33, P = 0.04, and PYY: r = -0.36, P = 0.02). After gastric Ensure, while both plasma CCK (P = 0.03) and PYY (P = 0.02) concentrations were higher in patients with delayed GE, there was a direct relationship between the rise in plasma CCK (r = 0.40, P = 0.01) and PYY (r = 0.42, P < 0.01) from baseline at 60 minutes after the meal and the GEC.. In critical illness, there is a complex interaction between plasma CCK, PYY, and GE. Whilst plasma CCK and PYY correlated moderately with impaired GE, the pathogenetic role of these gut hormones in delayed GE requires further evaluation with specific antagonists.

Topics: Cholecystokinin; Critical Illness; Female; Gastric Emptying; Humans; Male; Middle Aged; Peptide YY; Prospective Studies

Acute acalculous cholecystitis remains a diagnostic challenge in critically ill trauma patients. Laboratory studies are nonspecific and associated injuries or mental status changes may mask clinical signs and symptoms. We conducted a retrospective study to assess the utility of ultrasound in the diagnosis of acute acalculous cholecystitis. We hypothesized that ultrasound is inadequate as a screening tool for acute acalculous cholecystitis. The abdominal ultrasounds of all patients undergoing evaluation for acute acalculous cholecystitis in a 40-month period at our Level I trauma center were reviewed. Thickened gallbladder wall, pericholecystic fluid and emphysematous gallbladder were considered positive sonographic criteria. Sludge, cholelithiasis, and hydrops were considered suggestive. Patients who did not undergo cholecystectomy had their gallbladders evaluated either during subsequent laparotomy or at autopsy or they were discharged from the hospital without need for intervention. Sixty-two patients were included. Twenty-one patients underwent cholecystectomy for presumed acute acalculous cholecystitis. The data revealed a sensitivity of 30 per cent (6/20) and a specificity of 93 per cent (39/42) for ultrasound evaluation. Twenty patients had subsequent hepatobiliary scans [hepato-iminodiacetic acid (HIDA)] with a sensitivity of 100 per cent (12/12) and specificity of 88 per cent (7/8). Our data do not support ultrasound as a reliable routine screening tool for acute acalculous cholecystitis. Despite its convenience as a bedside procedure ultrasound has insufficient sensitivity to justify its use and a more sensitive diagnostic tool should be used.

Topics: Acute Disease; Adult; Cholecystectomy; Cholecystitis; Cholecystokinin; Comorbidity; Critical Illness; Humans; Imino Acids; Middle Aged; Radionuclide Imaging; Retrospective Studies; Ultrasonography; Wounds and Injuries