Enterohormones
concentrations during critical illness:
Prospective
observational trial (protocol)
C.A. Santacruz H1-2, 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
- 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.
-
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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