Amino Acid Nutrition in the Critically-ill

Study Overview
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Brief Summary
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Enhancing the anabolic effect of nutrition in critically ill patients by administering exogenous amino acids.

Detailed Description
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Critically-ill patients admitted to the intensive care unit are invariably catabolic and are commonly undernourished. Previous observational studies indicate that increased dietary administration of protein or essential amino acids might be associated with improved clinical outcomes. The investigators propose that the parenteral supplementation of intravenous amino acids in critically-ill patients will restore anabolic processes and that anabolism is associated with molecular markers of amino acid sensing and protein synthesis. The results from this study will establish biomarkers of anabolism (i.e., nutritional success) that can be used in future clinical trials on the use of amino acid supplementation in the critically-ill.

Official Title
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Enhancing the Anabolic Effect of Nutrition in Critically Ill Patients by Administering Exogenous Amino Acids

Conditions
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Malnutrition, Critical Illness, Inflammation

Intervention / Treatment
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* Dietary Supplement: Peptamen 1.5% via enteral
* Dietary Supplement: Prosol 20% IV to 1.75g/kg/day
* Dietary Supplement: Prosol 20% IV to 2.5g/kg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mechanically ventilated adult patients (>18 years old) admitted to ICU with an expected ICU dependency (alive and need for mechanical ventilation Vasopressor therapy, or mechanical circulatory support) at the point of screening of an additional 3 days, as estimated by the treating physician. Exclusion Criteria: Patients who are moribund (expected death within 48 hours) Expected to have life-sustaining treatments withdrawn in the next 3 days Those with a contraindication to enteral nutrition (EN) Already on parenteral nutrition (PN) Those with acute fulminant hepatitis or severe chronic liver disease (Child's class C) Patients on extracorporeal membrane oxygenation or carbon dioxide removal* Patients with organ transplantation Those with a broncho-pleural fistula Patients with documented allergies to any of the study nutrients or its excipients will be excluded. Patients requiring continuous renal replacement therapy or extracorporeal membrane oxygenation are excluded due to inability to accurately measure protein turnover.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1: Peptamen 1.5% via enteral only<br>Study patients in this group will be prescribed 1.0 g/kg/d of protein using standard EN Peptamen 1.5%. Based on current compliance or tolerance statistics, investigators expect patients to only receive 50-60% of these prescribed doses; effective protein intake will therefore be approximately 0.5-0.6 g/kg/d | Dietary Supplement: Peptamen 1.5% via enteral<br>* Study patients in this group will be prescribed 1.0 g/kg/d of protein using standard enteral Peptamen 1.5%. Based on current compliance or tolerance statistics, investigators expect patients to only receive 50-60% of these prescribed doses; effective protein intake will therefore be approximately 0.5-0.6 g/kg/d.<br>* Other names: Enteral feeding with Peptamen 1.5%;|
| Active Comparator: Group 2: Prosol 20% IV to 1.75g/kg/day<br>Patients in group 2 will receive the same enteral feeding as group 1 (Peptamen 1.5) but in addition will receive sufficient intravenous amino acid supplements (Prosol 20%) to achieve an effective fixed dose of 1.75 g/kg/d | Dietary Supplement: Peptamen 1.5% via enteral<br>* Study patients in this group will be prescribed 1.0 g/kg/d of protein using standard enteral Peptamen 1.5%. Based on current compliance or tolerance statistics, investigators expect patients to only receive 50-60% of these prescribed doses; effective protein intake will therefore be approximately 0.5-0.6 g/kg/d.<br>* Other names: Enteral feeding with Peptamen 1.5%;Dietary Supplement: Prosol 20% IV to 1.75g/kg/day<br>* Patients in group 2 will receive Peptamen 1.5% but in addition, will receive sufficient intravenous amino acid supplements (Prosol 20%) to achieve an effective fixed dose of 1.75 g/kg/day.<br>* Other names: Enteral feeding with Peptamen 1.5% plus Prosol 20%;|
| Active Comparator: Group 3: Prosol 20% IV to 2.5g/kg/day<br>Patients in this group will receive intravenous amino acids (Prosol 20%) in addition to standard enteral Peptamen 1.5% to achieve an effective protein intake of 2.5 g/kg/day. | Dietary Supplement: Peptamen 1.5% via enteral<br>* Study patients in this group will be prescribed 1.0 g/kg/d of protein using standard enteral Peptamen 1.5%. Based on current compliance or tolerance statistics, investigators expect patients to only receive 50-60% of these prescribed doses; effective protein intake will therefore be approximately 0.5-0.6 g/kg/d.<br>* Other names: Enteral feeding with Peptamen 1.5%;Dietary Supplement: Prosol 20% IV to 2.5g/kg/day<br>* Patients in this group will receive intravenous amino acids, Prosol 20% in addition to standard enteral Peptamen 1.5% to achieve an effective protein intake of 2.5 g/kg/d.<br>* Other names: Enteral feeding with Peptamen 1.5% plus Prosol 20%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole body protein balance | Primed continuous infusions of stable isotope tracers will be applied to assess dynamic changes in whole body and hepatic protein metabolism (i.e., protein breakdown, amino acid oxidation, protein synthesis, total protein, albumin and fibrinogen synthesis) before 48 hours after beginning the intervention. During the period of isotope infusion, nutrition will be held constant. A positive protein balance (difference between protein synthesis and protein breakdown) will be used as an indicator of whole body anabolism. All isotopes will be purchased from CDN Laboratories (Montreal, Canada). Sterile solutions will be tested to be free of pyrogens. Before beginning each experiment blood and expired air samples will be collected to determine baseline enrichments of [1-13C]-ketoisocaproate ([1-13C]-KIC), [6,6-2H2]glucose, L-[2H5]phenylalanine and expired 13CO2. Retention of H13CO3- in the bicarbonate pool will be measured in each patient using the approach of Kien. | 0 and 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Synthesis rates of hepatic secretory proteins (the total plasma protein pool, albumin, fibrinogen in %/d) | This will be measured from the rates of incorporation of L-[2H5] phenylalanine into the proteins using plasma very low density lipoprotein apolipoprotein-B100 (VLDL-apoB-100) isotopic enrichment at plateau to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes the other plasma protein. A priming dose of L-[2H5]phenylalanine (4 μmol/kg, iv) will be given followed by a six-hour infusion at 0.10 μmol/kg/min. At baseline, 3 hours, 4 hours, 5 hours, and 6 hours thereafter blood will be drawn, immediately transferred into pre-chilled tubes containing Na2EDTA and a protease inhibitor cocktail of sodium azide, merthiolate and soybean trypsin inhibitor, then centrifuged and stored at -70ºC for later analysis. 10 ml blood will be required for secretory protein synthesis studies. | 0 and 48 hours | 
| Biomarker of amino acid restriction or repletion - ELISA (pg/ml) | Blood (one 4-ml tube per sample) will be collected at baseline, then every 12 hours in the first 48 hours, and 72 hours post initiation of amino acid administration. Measures of amino acid-sensitive inflammation include the following: serum C-reactive protein and interleukin-6. | 0, 12, 24, 36, 48, 72 hours | 
| Biomarker of amino acid restriction or repletion - mRNA detection (copy number/ml) | Blood (one 2.5-ml tube per sample) will be collected at baseline, then every 12 hours in the first 48 hours, and 72 hours post initiation of amino acid administration. Using Pax-gene tubes, peripheral blood mononuclear cell (PBMC) mRNA will be isolated for detection of interleukin-6 and c-reactive protein gene expression. | 0, 12, 24, 36, 48, 72 hours | 
| Biomarker of amino acid restriction or repletion - protein levels (fold increase in Western blot band density) | Blood (one 4 ml cell separator tube per sample) will be collected at baseline, then every 12 hours in the first 48 hours, and 72 hours post initiation of amino acid administration. Measures of amino acid-sensitive cell signaling in peripheral blood mononuclear cells include: phospho- p70 S6 kinase, phospho-S6, or phospho-eiF2α by Western blot. | 0, 12, 24, 36, 48, 72 hours | 
| Metabolic Substrates (micromolar) | Plasma amino acids and markers of oxidative stress (glutathione, cysteine, related sulfhydryl) by liquid chromatography tandem mass spectroscopy. Blood will be collected at baseline, then at 24, 48, and 72 hours initiation of amino acid administration. | 0, 24, 36, 48, 72 hours | 
| Resting Energy Expenditure (kcal) | Investigators will measure resting energy expenditure by indirect calorimetry at the 5 hour time point of each tracer protocol (Baseline and 48 h after initiation of amino acid administration. This will permit comparison of actual energy expenditure with that estimated by weight-based nomogram used for nutritional dosing. | 0 and 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amino acids, critically-ill, catabolic, nutrition, anabolic