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Amino Acid Nutrition in the Critically-ill (AA-ICU)

Primary Purpose

Critical Illness, Inflammation, Malnutrition

Status
Recruiting
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Peptamen 1.5% via enteral
Prosol 20% IV to 1.75g/kg/day
Prosol 20% IV to 2.5g/kg/day
Sponsored by
Arnold Kristof
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Critical Illness focused on measuring Amino acids, critically-ill, catabolic, nutrition, anabolic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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  • Expected to have life-sustaining treatments withdrawn in the next 3 days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.

Sites / Locations

  • McGill University health CentreRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Group 1: Peptamen 1.5% via enteral only

Group 2: Prosol 20% IV to 1.75g/kg/day

Group 3: Prosol 20% IV to 2.5g/kg/day

Arm Description

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

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

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.

Full Information

First Posted
July 7, 2015
Last Updated
April 9, 2022
Sponsor
Arnold Kristof
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1. Study Identification

Unique Protocol Identification Number
NCT02865408
Brief Title
Amino Acid Nutrition in the Critically-ill
Acronym
AA-ICU
Official Title
Enhancing the Anabolic Effect of Nutrition in Critically Ill Patients by Administering Exogenous Amino Acids
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2017 (Actual)
Primary Completion Date
February 28, 2023 (Anticipated)
Study Completion Date
February 28, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Arnold Kristof

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Critical Illness, Inflammation, Malnutrition
Keywords
Amino acids, critically-ill, catabolic, nutrition, anabolic

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Group 1: Peptamen 1.5% via enteral only
Arm Type
Active Comparator
Arm Description
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
Arm Title
Group 2: Prosol 20% IV to 1.75g/kg/day
Arm Type
Active Comparator
Arm Description
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
Arm Title
Group 3: Prosol 20% IV to 2.5g/kg/day
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Peptamen 1.5% via enteral
Other Intervention Name(s)
Enteral feeding with Peptamen 1.5%
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Prosol 20% IV to 1.75g/kg/day
Other Intervention Name(s)
Enteral feeding with Peptamen 1.5% plus Prosol 20%
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Prosol 20% IV to 2.5g/kg/day
Other Intervention Name(s)
Enteral feeding with Peptamen 1.5% plus Prosol 20%
Intervention Description
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.
Primary Outcome Measure Information:
Title
Whole body protein balance
Description
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.
Time Frame
0 and 48 hours
Secondary Outcome Measure Information:
Title
Synthesis rates of hepatic secretory proteins (the total plasma protein pool, albumin, fibrinogen in %/d)
Description
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.
Time Frame
0 and 48 hours
Title
Biomarker of amino acid restriction or repletion - ELISA (pg/ml)
Description
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.
Time Frame
0, 12, 24, 36, 48, 72 hours
Title
Biomarker of amino acid restriction or repletion - mRNA detection (copy number/ml)
Description
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.
Time Frame
0, 12, 24, 36, 48, 72 hours
Title
Biomarker of amino acid restriction or repletion - protein levels (fold increase in Western blot band density)
Description
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.
Time Frame
0, 12, 24, 36, 48, 72 hours
Title
Metabolic Substrates (micromolar)
Description
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.
Time Frame
0, 24, 36, 48, 72 hours
Title
Resting Energy Expenditure (kcal)
Description
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.
Time Frame
0 and 48 hours
Other Pre-specified Outcome Measures:
Title
ICU length of stay
Description
Duration of ICU admission in days.
Time Frame
72 hours to 1 year
Title
Hospital length of stay
Description
Duration of ICU admission in days.
Time Frame
72 hours to 1 year
Title
Ventilator-free days in ICU
Description
Duration of stay in ICU off mechanical ventilation.
Time Frame
72 hours to 1 year
Title
Hospital-acquired infections.
Description
Number of hospital-acquired infections during the hospital admission.
Time Frame
72 hours to 1 year
Title
Mortality
Description
Death in hospital (binary value for dead or alive).
Time Frame
72 hours to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Arnold S Kristof, MDCM, FRCPC
Phone
501-934-1934
Ext
35251
Email
arnold.kristof@mcgill.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Josie Campisi, RN, CRC
Phone
514-934-1934
Ext
42408
Email
josie.campisi@muhc.mcgill.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Arnold S Kristof, MDCM, FRCPC
Organizational Affiliation
McGill University Health Centre/Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
McGill University health Centre
City
Montréal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Arnold Kristof, MD
Phone
514-934-1934
Email
arnold.kristof@mcgill.ca
First Name & Middle Initial & Last Name & Degree
Josie Campisi, MSc
Phone
514-934-1934
Ext
65542
Email
josie.campisi@muhc.mcgill.ca

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34920728
Citation
Omiya K, Sato H, Sato T, Wykes L, Hong M, Hatzakorzian R, Kristof AS, Schricker T. Albumin and fibrinogen kinetics in sepsis: a prospective observational study. Crit Care. 2021 Dec 17;25(1):436. doi: 10.1186/s13054-021-03860-7.
Results Reference
derived

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Amino Acid Nutrition in the Critically-ill

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