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Adequate nutrition of critically ill patients plays a key role in the modulation of metabolic response to stress.
This paper presents the development of a protocol for a randomized controlled trial (RCT) aimed at comparing clinical outcomes of patients in the intensive care unit (ICU) administered with standard and protein-fortified diet. Together with the RCT study protocol, the results of the observational analysis conducted to assess the feasibility of the RCT are presented.
An RCT on adult patients admitted to ICU and undergoing mechanical ventilation in the absence of renal or hepatic failure will be conducted. Patients enrolled will be randomized with an allocation rate of 1:1 at standard diet versus protein-fortified diet. The estimated sample size is 19 per arm, for a total of 38 patients to be randomized.
Enrollment began in January 2017. In the feasibility study, 14 patients were enrolled. Protein administration increased significantly (
Results of the feasibility study clearly confirmed that protein provision in ICU patients is below that recommended and that this results in impaired NB. The emerging of an interindividual variability in NB will be further analyzed in the RCT.
ClinicalTrials.gov NCT02990065; https://clinicaltrials.gov/ct2/show/NCT02990065 (Archived by WebCite at http://www.webcitation.org/6prsqZdRM).
In recent years, several studies have focused on the molecular and biological effects of nutrients in maintaining homeostasis in patients admitted in intensive care unit (ICU), and ad hoc recommendations have been developed for the assessment and provision of nutritional support in adult critically ill patients [
All patients admitted in ICU require a full nutritional assessment for determining both energy and protein requirements to prevent malnutrition. According to international guidelines [
In the critical setting, protein is the macronutrient most often lacking in such patients, and its supplementation is likely to result in beneficial effects [
This paper presents the development of a protocol for a randomized controlled trial (RCT) aimed at assessing changes of nitrogen balance (NB) in ICU patients administered with standard parenteral/enteral diet and protein-fortified parenteral/enteral diet. Together with the study protocol, results of the pilot study conducted to assess the feasibility of such a trial are also presented.
This study has been designed as a parallel arm RCT enrolling patients admitted at the Department of Anaesthesia and Intensive Care
Inclusion criteria:
Aged 18 years and older
Receiving parenteral nutrition or enteral nutrition
Having an indwelling catheter
Undergoing mechanical ventilation
Exclusion criteria:
Current or 6-month past history of gastrointestinal bleeding
body mass index <18.5 kg/m2 or ≥ 30 kg/m2
Terminal illness
Pregnancy
Acute renal failure defined using Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines [
Hepatic failure
Patients enrolled will be randomized to standard nutritional care (standard diet) to meet daily patient caloric requirement (control group) or appropriate amount of protein feeding (protein-fortified diet) to meet daily patient protein requirement (intervention group). Random allocation will be performed using a computer-generated algorithm (with an allocation rate of 1:1). Subjects enrolled will remain in the study until they are no longer mechanically ventilated. Participants will be blinded to treatment allocation. The flowchart of the study protocol is shown in
Flowchart of the study protocol.
The standard diet consists of an energy goal based on weight formula (20-25 kcal/kg/day). According to the ICU nutritional protocol, enteral nutrition (EN) will be started at an initial rate of 10 mL/h and increased by 20mL/h every 12 hours in the absence of significant gastric residuals (<250 mL), with the aim of reaching the energy goal within 72 hours of admission. The EN formulae used are standard (1-1.5 kcal/mL, 40 g/L protein). If EN is not tolerated or not indicated, supplemental parenteral nutrition (PN) will be used to make up the energy shortfall. The PN formula used is standard (1000 kcal/L, 37 g/L protein).
The protein-fortified diet consists of an energy goal based on REE and a protein target based on the most recent literature recommendations (1.2-2 g/kg/day) [
For the intervention group, EN will be started at an initial rate of 10 mL/h and increased by 20 mL/h every 8 hours in the absence of significant gastric residuals (<250 mL) with the aim of reaching the energy goal within 48 hours of admission. The EN formulae used are high in protein (1-1.5 kcal/mL, 74 g/L protein). If EN is not tolerated or not indicated, supplemental PN is used to make up the energy shortfall. The PN formula used will be arranged by the hospital pharmacy to meet the energy targets set for the intervention group.
For patients enrolled in the control group and the intervention group, gastric residuals will be checked 4 times per day and electrolytes will be closely monitored and replaced. Adequacy of nutritional support will be determined daily by measuring NB.
Age (years), gender, weight (kg), height (cm), body mass index (BMI) (kg/m2), main diagnosis, clinical history, and illness severity assessed using the Acute Physiology and Chronic Health Evaluation (APACHE) II score [
The following parameters will be recorded at midnight of each day: caloric intake, protein intake, measurement of 24-hour urine urea nitrogen (UUN) excretion, blood creatinine, NB, blood urea nitrogen (BUN) level, average blood glucose, amount of propofol administered (mL/day), amount of dextrose administered (mL/day).
A standard formula will be used for NB calculation [
Considering NB as primary outcome, a sample size estimation has been performed considering a
Data will be entered and managed using REDCap (Research Electronic Data Capture), a Web-based application for managing databases hosted at the Department of Cardiac Thoracic and Vascular Sciences, University of Padova (Italy).
The primary endpoint will be analyzed for the intention-to-treat (ITT) population. After having reached the sample size foreseen, a
The study was approved by the regional ethics committee of Friuli Venezia Giulia, Italy (CEUR-2016-Sper-066-ASUIUD). Each patient or legally authorized representative must provide written informed consent for the study procedures.
An observational analysis was conducted to assess the feasibility of the trial. This observational study enrolled patients admitted to the ICU
Our nutritional approach was led by current guidelines that recommend providing 25-30 kcal/kg/day. Both EN and PN were used to achieve energy goals. EN formula was the Nutrison standard (1000 kcal and 40 g of protein per 1000 mL); an all-in-one solution containing 1000 kcal and 47 g of protein per 1000 mL was used for PN.
Using REDCap, the following patient information were collected: admission diagnosis, comorbidities, age, sex, BMI, APACHE II score, SAPS II score (at baseline), type and amount of nutrition received (both caloric and protein intake), amount of propofol and dextrose (mL/day) administered, and blood chemistry (urea nitrogen level, creatinine, glucose) (at midnight of each day). A daily 24-hour urine collection was conducted in all patients and NB was calculated. For each patient, any infection or skin alteration occurring during the study period was reported. Daily data were collected until the end of mechanical ventilation or until renal/hepatic acute failure, death, or discharge from the ICU.
Continuous variables were reported as median (I quartile and III quartile), and discrete parameters were reported as absolute value (percentage). The distribution of the quantitative variables was summarized using simple barplots for trend. To assess if the series has an increasing or decreasing trend, a nonparametric Spearman test was performed between the observations and time. To calculate trends, means of patient measures of interest were considered. A
Enrollment in the study began in January 2017. Data collection is expected to be conducted until April 2017. Data analysis will start once the data collection is completed and the database is locked.
Sample characteristics are summarized in
Despite the increased provision of protein during hospitalization, the BUN significantly increased (
Finally,
Composition of the calories administered.
Characteristics of the patients enrolled in the feasibility study.
Characteristics | Number | ||
Age (years), median (I and III quartile) | 48 (43-55) | ||
Male | 8 (57) | ||
Female | 6 (46) | ||
Weight (kg), median (I and III quartile) | 83 (66-94) | ||
BMIa(kg/m2), median (I and III quartile) | 25.5 (24.2-27) | ||
APACHEbII score, median (I and III quartile) | 10.5 (9-16) | ||
SAPScII score, median (I and III quartile) | 29 (24-36) | ||
Observation period (days), median (I and III quartile) | 8 (6-12) | ||
Organ failure | 4 (29) | ||
Respiratory failure | 3 (75) | ||
Sepsis and infection | 1 (25) | ||
Trauma | 6 (43) | ||
Multiple trauma | 5 (83) | ||
Spinal trauma | 1 (17) | ||
Cerebrovascular disease | 4 (29) | ||
Cerebral hemorrhage | 2 (50) | ||
Coma | 2 (50) | ||
Cerebrovascular accident | 3 (21) | ||
Chronic obstructive pulmonary disease | 1 (7) | ||
Diabetes | 2 (14) | ||
Hypertension | 3 (21) | ||
Smoking | 2 (14) | ||
Anxiety/depression | 2 (14) | ||
Neoplasia | 1 (7) | ||
Transfer to another hospital | 2 (14) | ||
Term of mechanical/spontaneous breathing | 8 (57) | ||
Acute renal or hepatic failure | 3 (21) | ||
Death | 1 (7) |
aBMI: body mass index.
bAPACHE: Acute Physiology and Chronic Health Evaluation.
cSAPS: Simplified Acute Physiology Score.
Protein intake trend.
Blood urea nitrogen trend.
Cumulative nitrogen balance during the first 72 hours.
Protein intake administered versus ideal protein target in the first 24 hours.
In recent years, several studies have focused on the importance of an adequate caloric intake in critically ill subjects. However, specific evidence about protein intake (adequate amount to be administered, adverse outcomes associated with inadequate protein intake) is sparse, even though several studies have demonstrated that in critically ill patients protein breakdown is greatly increased [
Considering this framework, the main issue in the nutritional management of ICU patients is represented not only by the identification of the most adequate daily caloric intake but also by the identification of the optimal contribution of each nutrient to the daily caloric intake, focusing particularly on protein content. The aim of our study protocol is to provide evidence about the effectiveness of a protein-fortified diet in patients admitted to ICU.
To assess the feasibility of this study protocol, a pilot study was conducted. Consistent with previous research [
Although the NB was negative in all patients, we observed that cumulative NB in the first 72 hours was different among subjects observed. This is probably due to an interindividual variability in the lean body mass that results in a different amount of protein metabolism waste. Beyond its action on protein metabolism, dietary protein intake affects body composition [
Weight-based equations (1.2-2 g/kg/day) may be used to monitor adequacy of protein provision [
Even though several studies have shown that the provision of an appropriate protein intake may reduce net muscle catabolism, to our knowledge this is the first study protocol aimed at comparing clinical outcomes of standard and protein-fortified diet in an ICU population. Results of the feasibility study clearly confirmed that protein provision in ICU patients is below that recommended in international guidelines and that this results in impaired NB. Moreover, it provided evidence that protein catabolism is different among patients, probably due to differences in body composition (eg, lean body mass). Such interindividual variability will be further analyzed in the trial to understand if and how it may be considered in the titration of protein intake.
Energy and protein intake calculation for intervention group only.
Peer review and approval from Etichs Committee.
Acute Physiology and Chronic Health Evaluation
body mass index
blood urea nitrogen
enteral nutrition
Harris-Benedict equation
indirect calorimetry
intensive care unit
intention-to-treat
Kidney Disease Improving Global Outcomes
nitrogen balance
parenteral nutrition
randomized controlled trial
Research Electronic Data Capture
resting energy expenditure
Simplified Acute Physiology Score
urine urea nitrogen
None declared.