Enterohormones concentrations during critical illness:

Prospective observational trial (protocol)

C.A. Santacruz H^1-2, JC. Preiser¹.

1 Department of Intensive Care, Hopital Erasme, Brussels, Belgium.

Department of Intensive Care, Erasme University Hospital,

2. Fundación CardioInfantil, Cardiovascular intensive care unit, Bogota, Colombia

INTRODUCTION

Critical illness-related decrease in food intake can be an adaptive component of the stress response, partially mediated by hormones released from the gastrointestinal tract, i.e. enterohormones (1, 2). These enterohormones include peptide YY (PYY), ghrelin, which are actively involved in the regulation of appetite, the anterograde propulsion of the alimentary bolus, secretion and absorption of nutrients (2).

In the critically ill, gastrointestinal failure (GIF) is a common finding associated with alterations in all phases of food intake (3,4), and increased concentrations of PYY as compared (31.5 ± 9.6 pmol/l in critically ill patients versus 11.3 ± 1.0 pmol/l, in healthy subjects, p < 0.05). PYY is known for its anorexigenic effects on food intake (7,8).  Conversely, ghrelin has profound orexigenic properties, participating in hormonal and metabolic responses to fasting (9). Ghrelin levels in critically ill patients are low as compared to controls (day one 297.8 ± 76.3 versus 827.2 ± 78.7 pmol/l, p < 0.001, respectively)(8). During the prandial phase, ghrelin hormone is intrinsically involved in gastrointestinal anterograde contraction (8,9). Low levels of ghrelin could increase the risk of enteral nutrition intolerance due to delayed gastric emptying and to complications such as vomiting and bronco-inhalation (10,11). In fact, analogs of ghrelin and other enterohormones are now used as an adjunctive treatment for patients with short bowel syndrome, diabetes mellitus-induce gastroparesia, renal failure, liver failure, or chronic heart failure (13,14).

However, the relationship between plasma concentrations of PYY or ghrelin and signs of GIF, have not been accurately documented in critically ill patients. This prospective observational trial aims to search for an association between the concentration and time course of PYY and Ghrelin and the tolerance to enteral nutrition. More specifically, signs of enteral intolerance  (e.g. gastric residual volume higher than a threshold value, diarrhea, vomiting) will be recorded in patients admitted to the intensive care unit for > 3 days and a correlation with the plasma concentration of PYY and ghrelin will be searched. We hypothesize that in case of intolerance to enteral nutrition the concentrations of PYY will be higher and the concentrations of ghrelin will be lower than in food-tolerant patients.

HYPOTHESIS

We hypothesize that in case of enteral nutrition intolerance, the concentrations of PYY will be higher and the concentrations of ghrelin will be lower than in food-tolerant patients.

OBJECTIVES

 

-       To compare the plasma concentrations of PYY and ghrelin of critically ill patients with healthy controls.

-       To evaluate the relationship between daily plasma PYY and ghrelin concentrations during ICU stay (or up to day 7) in all patients with an expected ICU-LOS > 3 days on the outcome of enteral feeding intolerance (e.g. gastric residual volume >250 mL/24 hours, enteral nutrition induced diarrhea, vomiting).

-       To evaluate the relationship between ghrelin and PYY hormones serum concentration and other outcome variables:  rate of infection, ventilator free days (VFD), intensive care unit length of stay (ICU-LOS), multiple organ dysfunction (MOD) and all-cause mortality.   

MATERIALS AND METHODS

1. Inclusion criteria

-       All ICU admissions with an expected (ICU-LOS) >3 days (according to physician criteria).

-       Prescription of enteral nutrition.

2. Exclusion criteria

-       Contraindication to enteral feeding.

-       Pediatric patients (<18 years).

-       Pregnant patients.

-       Patients with imminent death.

3. Interventions

-       5 mL venous blood per day for 5 days.

4. Outcome variables

·      Serum concentration of ghrelin and PYY.

·      Residual gastric volume (mL).

·      Episodes of diarrhea and vomiting.

·      Rate of VAP, catheter associated urinary track infection, central venous catheter associated infection, blood stream infections, etc. as defined by the CDC.

·      Ventilator free days (VFD).

·      Organ support free days

·      Intensive care unit length of stay (ICU-LOS).

·      Multiple organ dysfunction (MOD) as measured by the SOFA score.

·      All-cause mortality.  

·      APACHE II

·      Daily SOFA

 5. Definitions

-       Enteral nutrition tolerance period: time (days) for each patient during ICU stay with < 250 mL/day of gastric residual volume, no vomiting and no diarrhea (>3 liquid stools/day).

-       Enteral nutrition intolerance (ENI) (8): time period (days) for each patient during ICU stay with vomiting or high gastric residual volume > 250 mL + diarrhea (>3 liquid stools/day).

-        Days with GI intolerance: number of days with ENI as opposed to the number of days without ENI in the same patient.

-       Residual volume: Residual gastric volume was measured by aspiration through the nasogastric tube (15-Fr) using a 50-mL syringe according to ICU policies.

-       Vomiting: vomiting is defined as gastric contents detected in the oropharynx or outside the mouth.

-       VAP: new and persistent or progressive infiltrates on the chest radiograph with at least 2 of the following criteria: peripheral leukocytosis (>10 000/mL), leukopenia (<4000 cels/mL), body temperature of at least 38.5°C or of 35.5° C or less, and purulent tracheal aspirates, positive quantitative bacteriologic cultures of distal respiratory specimens obtained by bronco-alveolar lavage (significant bacterial count threshold of 10⁴ colony-forming units [cfu]/mL), or tracheobronchial aspirate (significant threshold of 10⁵ cfu/mL) (14).

-       VFD: number of consecutive days without ventilator support days 48 hours after successful weaning from mechanical ventilation.

-       Organ support free days: number of days without mechanical ventilation, renal replacement therapy, vasopressors, or extracorporeal hemodynamic support.

-       ICU-LOS: Days spent in the ICU from day to admission to decision to transfer to a general ward.

-       MOD: organ dysfunction as assessed by daily SOFA score during ICU stay.

-       Mortality: number of deaths during ICU hospitalization from any cause.

6. Serum sampling, ELISA and Western blot

To assure optimal sampling of ghrelin and PYY in serum, all measurement will follow international recommendations (15) as follows:

-    The collection of blood samples with EDTA–aprotinin is preferred.

-       Blood samples should be chilled (4°C) and centrifuged as soon as possible, at least within 30 min after collection.

-       Because acidification is the best method for the plasma preservation of ghrelin, the plasma sample can be added to 1 mol/l HCl (10% of volume) for adjustment to pH 4.

6. Clinical data: (recorded daily until D5)

Along with serum samples, several clinical data will be collected:

-       Age: in years.

-       Sex: male/female.

-       Category of admission: traumatic, medical, and surgical.

-       Time to initial medical attention.

-       Glasgow Coma Scale.

-       All available hemodynamic data and vasopressor use.

-       All available respiratory and mechanical ventilation data.

-       All available data on renal function.

-       All available data on metabolic and nutritional support.

-       All available data on neurologic function.

-       Intra-abdominal pressure measured accordingly to international standards.

-       Nutritional risk screening (>3: at nutritional risk).

-       Time on vasopressor use (days).

-       Time to enteral nutrition initiation (hours from admission).

-       Time to achieving 75% of total enteral caloric prescribed Kcal (20-25 Kcal/Kg/day).

-       Residual gastric volume (mL/day).

-       Intra-abdominal pressure (mmHg).

-       Vomiting (No. episodes).

-       Diarrhea (No. episodes).

-       Complete laboratory and radiologic data during the study period (blood glucose, imaging, cultures etc.)

7. Ethical issues

The study complies with the declaration of Helsinki and Good clinical practices laws and with the bill to collect human biological material for human scientific research purposes. This trial is considered in the MCH category. Approval by local ethical committee and an informed consent for use of the human body fluids will be obtained from the patient or from the legal guardian.

8. Statistical analysis:

All statistical analyses will be made using R software v.3.2.1. The numerical results will be given as median value ± standard deviation, or as median and interquartile range, accordingly. Categorical variables will be compared using a Fisher exact test or Chi square test. Continuous variables will be analyzed based on their distribution. Normally distributed variables will be compared using a Student’s t-test or ANOVA test. Non-normally distributed variables will be analyzed with a Mann Whitney test or Wilcoxon. Repeated measurements will be analyzed using mixed models procedure. Multivariate analysis will be carried out by means of logistic regression. Correlation between serum ghrelin/PYY and outcomes will be done using the Pearson or Spearman test accordingly, stratified by enteral nutrition tolerance or intolerance during ICU-stay.

IMPLICATIONS OF THIS STUDY

Enteral nutrition intolerance and related complications during ICU hospitalization are important risk factors for increase morbidity, prolonged stay and resource utilization. Understanding the pathophysiology of enterohormones during critical illness may help in the development of treatment strategies to treat enteral nutrition intolerance in subgroups of at risk patients.

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