EAL

CI: Supplemental Intravenous Glutamine (2011)

Citation:

Griffiths RD, Allen KD, Andrews FJ, Jones C. Infection, multiple organ failure, and survival in the intensive care unit: Influence of glutamine-supplemented parenteral nutrition on acquired infection. Nutrition. 2002 Jul-Aug; 18(7-8): 546-552.

PubMed ID: 12093428

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

Investigate the effect of GLN-supplemented PN on types and rates of intensive care acquired infection.

Inclusion Criteria:

Patients in the European Prevalence of Infection in Intensive Care (EPIC) study that received PN while in ICU.

Exclusion Criteria:

Patients in the intensive care unit not receiving PN.

Description of Study Protocol:

Recruitment

Data are from the European Prevalence of Infection in Intensive Care (EPIC) study reported.

Design

Double-blind, randomized, controlled trial in an adult general intensive care unit.

Blinding Used

Double blind.

Intervention

In the intervention group, PN was supplemented with an average of 20g of exogenous glutamine (supplementation ranged between 17 and 24g per day)
The control group received isonitrogenous, isoenergetic total parenteral nutrition.

Statistical Analysis

Comparisons were made between medians and interquartile ranges with the Mann-Whitney U-test
Proportions were tested with Fisher's exact test (chi squared test with Yates' continuity correction, two-tailed) and survival curves were compared with the log rank test
Binary logistic regression was used to test the relationship between glutamine and the incidence of the first intensive-care acquired infection after starting total parenteral nutrition.

Data Collection Summary:

Timing of Measurements

Clinical and microbiological data were collected on all new infective episodes and associated treatment decisions.

Dependent Variables

Intensive-care acquired infection
Mortality.

Independent Variables

PN formula supplemented with GLN or isocaloric, isonitrogenous control formula.

Description of Actual Data Sample:

Initial N: 84 (56% male) general adult ICU patients
Attrition (final N): Same
Age: Median ages 65 and 63 for GLN and control PN groups, respectively
Demographic Information: APACHE II median (IQR) for GLN and control groups were 18 (14 to 22) and 17 (13 to 22), respectively
Location: England.

Summary of Results:

Key Findings

Variables	Patients Receiving More than Five Days Total Parenteral Nutrition Plus Glutamine Supplementation (N=25)	Patients Receiving More than Five Days Total Parenteral Nutrition Control (N=27)	P-value
N (%) patients developing intensive-care acquired infection	21 (84%)	20 (74%)	Not significant
N intensive-care acquired infections after five days of total parenteral nutrition	25	38	Not significant
N (%) patients developing intensive-care acquired infection after starting total parenteral nutrition	19 (76%)	20 (74%)	Not significant
Mortality in ICU	8 (32%)	16 (59%)	Not significant
Mortality at six months	9	18	P<0.05

Difference in the number of infective episodes between patients receiving glutamine for at least five days and patients in the control group was not statistically significant
No differences in the proportion of gram-positive and gram-negative organisms causing intensive-care acquired infection between groups receiving total parenteral nutrition for at least five days
Sites of infection were similar for both groups except for the incidence of bacteremia and proven catheter infections; there were 21 catheter-related infections in 27 control patients receiving total parenteral nutrition for at least five days, and only 12 catheter-related infections in 27 patients receiving total parenteral nutrition plus glutamine for at least five days
No statistically significant difference in incidence of Candida infection in both groups receiving total parenteral nutrition for at least five days
Although not statistically significant, after five days of total parenteral nutrition the glutamine patients had only 25 infective episodes, compared with 38 infective episodes in the control group
A significantly smaller proportion of ICU-acquired infections after the start of total PN were associated with ICU death in the glutamine recipients; 15 of 40 infections were in the glutamine patients who died compared with 37 of 50 infections in the control patients who died (P<0.0006)
Glutamine, but not incidence of intensive-care acquired infection, was significantly associated with improved six-month survival (P<0.027)
Patients who developed intensive-care acquired infection and received glutamine for at least five days showed a trend to better ICU survival and six-month survival (P<0.06)
Glutamine patients fed for at least five days showed significantly better survival to six months; nine of 25 in the glutamine group vs. 18 of 27 in the control group had died (P<0.05)
Relative risk for death was 0.67 in the glutamine group vs. 1.38 for the control group (P<0.05), producing a hazard ratio of 0.47 (0.22 to 1.0, 95% CI) in favor of glutamine.

Other Findings

The incidence of Candida infection was halved in the glutamine group (N=4 in glutamine group vs. N=9 in control group), even though the admission predicted risk of death was higher in the glutamine group (53% in the glutamine group, 44% in the control group). It took longer for Candida infection to develop in the glutamine group (18 days in ICU to first Candida infection in the glutamine group vs. 11 days in the control group).

Author Conclusion:

Incidence of ICU-acquired infections is not reduced in patients who have GLN-supplemented PN, but risk of dying may be lessened.

Funding Source:

Industry:

Oxford Nutrition (UK) and Fresenius- Kabi (Sweden)

Pharmaceutical/Dietary Supplement Company:

Not-for-profit

Sir Jules Charitable Trust (UK) and The Stanley Thomas Johnson Foundation (Geneva)

Reviewer Comments:

This study was done from data collected during another randomized, controlled trial. Although the authors discuss follow-up and six-month mortality, the timing, method and measurement of follow-up is not discussed. A limitation mentioned by the authors is that it was not possible in this study to assess the severity of each intensive-care acquired infection and subsequent contribution to risk of death.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	???
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	???