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Trial registered on ANZCTR

Registration number

ACTRN12614001094662

Ethics application status

Approved

Date submitted

24/09/2014

Date registered

15/10/2014

Date last updated

15/10/2014

Type of registration

Retrospectively registered

Titles & IDs

Public title

Glutamine kinetics in intensive care unit patients – relation between plasma concentration and endogenous production

Scientific title

Observational study of the relation between plasma glutamine concentration and endogenous production in ICU patients.

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1162-1906

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Low plasma glutamine and critical illness

High plasma glutamine and critical illness

Liver failure

Condition category

Condition code

Metabolic and Endocrine

Other metabolic disorders

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

To measure endogenous glutamine production in ICU patients by a previously verified bolus injection method (Mori et al. PLoS One 2014 8;9(5) e96601). Subjects will receive a bolus injection of both glutamine and phenylalanine labeled with a stable isotope (1-13C-glutamine 3 mg/kg; ring2H5-phenylalanine 0.3 mg/kg). Bolus will be given over 20 seconds followed by 60 blood samples over 90 min to get a decay curve. Initially 1 sample every 30 sec, then every 60 sec and finally every 3 min. Each blood sample is 0,5 mL. During the measurement nutrition should be constant; to achieve this nutrition will not be altered two hours prior to the measurement or during the 90 minutes that blood samples are collected.
Four different groups will be studied:
1. 20 patients with low plasma glutamine (<420 umol/L) at admission to the ICU.
2. 20 patients with high plasma glutamine (>900 umol/L) at admission to the ICU.
3. 20 patients staying >5 days in the ICU.
4. 20 patients with high plasma glutamine (>900 umol/L) at admission to the ICU and liver failure.
Group 1 and 2 will be measured once in the first week of ICU stay. Group 3 will be measured several times with 3-5 days intervals. Group 4 will be measured several times with 2-3 days intervals. A subject may be included in more than one group.

Intervention code [1]

Not applicable

Comparator / control treatment

No control treatment.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Glutamine endogenous production or synthesis is assessed with injection of a small amount of labeled glutamine (labeled with a stable isotope; 13C). By taking frequent plasma samples and analyzing these for the decay of the labeled glutamine the endogenous production of glutamine can be analyzed by dividing the bolus dose of labeled glutamine by the area under the curve for the decay in plasma.

Timepoint [1]

First week of ICU stay. Measured over 90 minutes on one occasion only in groups 1 and 2, on 1-2 occasions in Group 3, and on 2-3 occasions in Group 4.

Secondary outcome [1]

Change in glutamine synthesis during ICU stay. Endogenous production is assessed with injection of a small amount of labeled glutamine (labeled with a stable isotope; 13C). By taking frequent plasma samples and analyzing these for the decay of the labeled glutamine the endogenous production of glutamine can be analyzed by dividing the bolus dose of labeled glutamine by the area under the curve for the decay in plasma.
Several measurements are made for groups 3+4. These will be compared to see if there is a change over time.

Timepoint [1]

2-5 days after previous measurement as long as in the ICU (maximum 3 measurements/2 week period).

Secondary outcome [2]

Glutamine de novo production and production from protein breakdown.
Glutamine endogenous production is coming from 2 sources; de novo synthesis and from breakdown of protein. To distinguish between the two we will assess whole body protein breakdown using a labeled phenylalanine (2H5-phenylalanine) in the same way as for the labeled glutamine (phenylalanine endogenous production is calculated from bolus divided by area under the curve for plasma 2H25-phenyalanine). Since phenylalanine is an essential amino acid its endogenous production can only come from protein breakdown. By assuming a ratio of phenylalnine to glutamine content in whole body protein the amount of glutamine coming from protein breakdown can be estimated. By subtracting the glutamine coming from protein breakdown from the total glutamine endogenous production, de novo production of glutamine is calculated (as in Mori et al Crit Care 2014 14;18(2)R72).

Timepoint [2]

First week of ICU stay and 2-5 days after previous measurement as long as in the ICU (maximum 3 measurements/2 week period).

Eligibility

Key inclusion criteria

Group 1: Plasma glutamine <420 umol/l at admission to the ICU.
Group 2: Plasma glutamine >900 umol/l at admission to the ICU.
Group 3: Expected length of stay in ICU >5 days.
Group 4: Plasma glutamine >900umol/l at admissio to the ICu and liver failure.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Absence of informed consent.

Study design

Purpose

Natural history

Duration

Cross-sectional

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

To detect a 25% difference in endogenous glutamine production rates between group 1 and 2 (primary outcome) with a 80% power, 19 patients are needed in each group based on variation in previous study in similar patients (Mori et al Crit Care 2014 14;18(2)R72).

Since repeated measures of glutamine endogenous production are not performed before we do not know the variation and will not be able to calculate power on the groups with repeated measures. The comparison between the low and the high glutamine production is the key question and therefore the study is powered to answer this question. The other groups are of the same size as an pragmatic approach and will give us data to in future studies calculate power also for repeated measurements. However since the repeated measurements will allow us to use paired analyses, the obtained higher power will most likely make this part of the study over powered rather than under powered.

Primary analysis: For comparison between group 1 and 2 using t-test or Mann-Whitney.
For repeated measurements ANOVA.

Secondary analysis: Regression analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

25/09/2014

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

Sweden

State/province [1]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Supported by grants provided by the Stockholm County Council (ALF project)

Address [1]

Stockholm County Council
Box 22550
SE-104 22 Stockholm
Sweden

Country [1]

Sweden

Primary sponsor type

Individual

Name

Jan Wernerman

Address

Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC)
and
Dept. Anesthesiology and Intensive Care, B31
Karolinska University Hospital Huddinge
SE-141 86 Stockholm, Sweden

Country

Sweden

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Regional Ethical Board in Stockholm

Ethics committee address [1]

Regionala etikprovningsnamnden i Stockholm
FE 289
171 77 STOCKHOLM

Ethics committee country [1]

Sweden

Date submitted for ethics approval [1]

Approval date [1]

19/02/2014

Ethics approval number [1]

2014/68-31/2

Summary

Brief summary

A low plasma concentration of glutamine at ICU admission is associated with an unfavorable outcome. A high glutamine concentration at ICU admission may also communicate a negative prediction. Exogenous glutamine supplementation normalizes plasma concentration and has been found to improve mortality outcome in the Scandinavian Glutamine Trial (Wernerman et al, Acta Anesth Scand 2011;55:812-18). However, the recent REDOX study showed a harmful effect of high doses of glutamine supplemented both parenteral and enteral (Heyland et al, NEJM 2013;368:1489-97). 
In an earlier study we have found that a small group of patients with high glutamine concentration at ICU admission had a higher 6-month mortality (Rodas Castillo et al, Clin Sci 2012;122:591-97). The group was too small to identify any other characteristics in the patients. However, acute liver failure was a diagnosis found within the subgroup. In another, still unpublished, study we have studied plasma glutamine concentration in patients with different kinds of hepatic insufficiency. The results show that both patients with acute fulminant liver failure and decompensated chronic liver failure have high glutamine concentrations. 
In order to be able to offer our ICU patients glutamine supplementation without risking an overdose by treating patients with normal plasma concentration,  we have a machine (BioProfile Analyser from Nova Biochemical) which can analyze glutamine concentration in blood and plasma within minutes. 
We have previously studied endogenous glutamine production in ICU patients given intravenous glutamine supplementation (Mori et al, Crit Care. 2014 14;18(2)R72). With this study we intend to use the same method to study specific groups of ICU patients to elucidate if the abnormal plasma glutamine concentrations are related to alterations in endogenous production.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Jan Wernerman

Address

Karolinska Institutet, Department of Clinical Science, Intervention and Technology (CLINTEC) and Dept. Anesthesiology and Intensive Care, B31 Karolinska University Hospital Huddinge SE-141 86 Stockholm, Sweden

Country

Sweden

Phone

+46 8 58 58 00 00

Fax

jan.wernerman@karolinska.se

Contact person for public queries

Name

Marie Smedberg

Address

Dept. Anesthesiology and Intensive Care, B31 Karolinska University Hospital Huddinge SE-141 86 Stockholm, Sweden

Country

Sweden

Phone

+46 8 58 58 00 00

Fax

marie.smedberg@karolinska.se

Contact person for scientific queries

Name

Marie Smedberg

Address

Dept. Anesthesiology and Intensive Care, B31 Karolinska University Hospital Huddinge SE-141 86 Stockholm, Sweden

Country

Sweden

Phone

+46 8 58 58 00 00

Fax

marie.smedberg@karolinska.se

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Endogenous production of glutamine and plasma glutamine concentration in critically ill patients.	2020	https://dx.doi.org/10.1016/j.clnesp.2020.09.015

N.B. These documents automatically identified may not have been verified by the study sponsor.

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