Critical Illness, Multiple Organ Failure, Sepsis
Conditions
Keywords
randomized trial, antioxidants, glutamine, organ failure
Brief summary
The purpose of this study is to determine whether providing high dose glutamine and antioxidants to critically ill patients will be associated with improved survival.
Detailed description
Background: Critically ill patients experience a degree of hyperinflammation, cellular immune dysfunction, and oxidative stress. Supplementation with key nutrients, like glutamine and antioxidants, is most likely to have a favourable effect on these physiological parameters leading to an improvement in clinical outcomes. The results of two separate meta-analyses suggested that glutamine and antioxidants may be associated with improved survival. We have recently completed a dosing study to determine the maximal tolerable dose (MTD) of glutamine dipeptides and antioxidants in critically ill patients with evidence of hypoperfusion. The purpose of this protocol is to evaluate the effect of high dose glutamine and antioxidant supplementation on mortality in a large scale randomized trial. Study Intervention: Patients will be randomized to receive glutamine supplementation or antioxidant supplementation (or respective placebo).
Interventions
OTHERGlutamine
0.35 gm/kg/day parenterally and 30 gms/day enterally
OTHERAntioxidants
500 micrograms of selenium/day parenterally and selenium 300 microgram, zinc 20 mg, beta carotene 10 mg, vitamine E 500 mg and vitamin C 1500 mg per day enterally
OTHERGlutamine + Antioxidants
0.35 g/kg/day glutamine parenterally and 30 g/day of glutamine enterally. 500 mcg selenium parenterally plus the following administered enterally: selenium 300 mcg, zing 20 mg, beta-carotene 10 mg, vitamin E 500 mg and vitamin C 1500mg
OTHERPlacebo
Normal saline intravenously and EN placebo formula (from Fresenius Kabi, Germany)
Sponsors
Fresenius Kabi
Daren K. Heyland
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Mechanically ventilated patients \> or = 18 years old * 2 or more organ failures related to acute illness
Exclusion criteria
* \> 24 hours from admission to ICU * Patients who are moribund * Lack of commitment to aggressive care * Absolute contraindication to enteral nutrients * Severe acquired brain injury * Routine elective cardiac surgery * Primary admission of burns \> 30% body surface area * Weight \< 50 kgms or \> 200 kgms * Pregnant or lactating patients * Previous randomization in this study * Enrollment in a related ICU interventional study * Child's class C liver disease * Metastatic cancer with life expectancy \< 6 months * Seizure disorder requiring anticonvulsant medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day Mortality | Day 28 | 28-day mortality/status: at 28 days after randomization; |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ICU Length of Stay | Day 28 | Measure of the duration of participant stay in the ICU |
| ICU Acquired Infection | Day 28 | We have made some modifications the definitions developed by the International Sepsis Forum Consensus Conference (CCM 2005;33:1538-1548) to operationalize the adjudication of infections in this trial. We grade the certainty of the diagnosis of infection using definitions for 'Definite', 'Probable', and 'Possible' for each category of infection. The categories of infection are: Deep surgical wound infection, Incisional (or superficial) surgical wound infection, Skin and soft-tissue infection (non-surgical) (SSTS), Catheter-related blood stream infections (CRI), Primary blood stream infections (BSI), Lower urinary tract infection, Upper urinary tract infection, Intra abdominal infection, Sinusitis, Lower respiratory tract infection (excluding pneumonia), ICU Acquired Pneumonia and Other. |
| Hospital Length of Stay | 6 months (from ICU admission) | Measure of the duration of the participant's hospital stay |
Countries
Belgium, Canada, Germany, Switzerland, United States
Participant flow
Recruitment details
This trial was conducted between April 2005 and December 2011 in 40 ICUs in participating countries after local jurisdictional and institutional Research Ethics Board approval.
Pre-assignment details
Written informed consent was obtained from patients or their legal representatives before enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Glutamine Glutamine supplementation | 301 |
| Antioxidants Antioxidant supplementation | 307 |
| Glutamine + Antioxidants Glutamine and antioxidant supplementation | 310 |
| Placebo Non-isonitrogenic, iso-caloric placebo solution | 300 |
| Total | 1,218 |
Baseline characteristics
| Characteristic | Glutamine | Antioxidants | Glutamine + Antioxidants | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 140 Participants | 151 Participants | 165 Participants | 141 Participants | 597 Participants |
| Age, Categorical Between 18 and 65 years | 161 Participants | 156 Participants | 145 Participants | 159 Participants | 621 Participants |
| Age, Continuous | 62.5 years STANDARD_DEVIATION 15 | 63.6 years STANDARD_DEVIATION 14.3 | 64.3 years STANDARD_DEVIATION 14 | 62.8 years STANDARD_DEVIATION 13.7 | 63.3 years STANDARD_DEVIATION 14.3 |
| Region of Enrollment Belgium | 1 participants | 2 participants | 5 participants | 2 participants | 10 participants |
| Region of Enrollment Canada | 259 participants | 262 participants | 263 participants | 260 participants | 1044 participants |
| Region of Enrollment Germany | 6 participants | 6 participants | 5 participants | 4 participants | 21 participants |
| Region of Enrollment Switzerland | 3 participants | 3 participants | 3 participants | 3 participants | 12 participants |
| Region of Enrollment United States | 32 participants | 34 participants | 34 participants | 31 participants | 131 participants |
| Sex: Female, Male Female | 110 Participants | 130 Participants | 130 Participants | 122 Participants | 492 Participants |
| Sex: Female, Male Male | 191 Participants | 177 Participants | 180 Participants | 178 Participants | 726 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 301 | 0 / 307 | 0 / 310 | 0 / 300 |
| serious Total, serious adverse events | 14 / 301 | 11 / 307 | 11 / 310 | 10 / 300 |
Outcome results
Primary
28-day Mortality
28-day mortality/status: at 28 days after randomization;
Time frame: Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Glutamine | 28-day Mortality | 97 participants |
| Antioxidants | 28-day Mortality | 89 participants |
| Glutamine + Antioxidants | 28-day Mortality | 101 participants |
| Placebo | 28-day Mortality | 76 participants |
Secondary
Hospital Length of Stay
Measure of the duration of the participant's hospital stay
Time frame: 6 months (from ICU admission)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glutamine | Hospital Length of Stay | 17.1 days |
| Antioxidants | Hospital Length of Stay | 16.0 days |
| Glutamine + Antioxidants | Hospital Length of Stay | 16.9 days |
| Placebo | Hospital Length of Stay | 16.5 days |
Secondary
ICU Acquired Infection
We have made some modifications the definitions developed by the International Sepsis Forum Consensus Conference (CCM 2005;33:1538-1548) to operationalize the adjudication of infections in this trial. We grade the certainty of the diagnosis of infection using definitions for 'Definite', 'Probable', and 'Possible' for each category of infection. The categories of infection are: Deep surgical wound infection, Incisional (or superficial) surgical wound infection, Skin and soft-tissue infection (non-surgical) (SSTS), Catheter-related blood stream infections (CRI), Primary blood stream infections (BSI), Lower urinary tract infection, Upper urinary tract infection, Intra abdominal infection, Sinusitis, Lower respiratory tract infection (excluding pneumonia), ICU Acquired Pneumonia and Other.
Time frame: Day 28
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Glutamine | ICU Acquired Infection | All Infections | 183 participants |
| Glutamine | ICU Acquired Infection | Microbiological Confirmed | 92 participants |
| Glutamine | ICU Acquired Infection | Infections classified as 'definite' or 'probable' | 118 participants |
| Antioxidants | ICU Acquired Infection | All Infections | 166 participants |
| Antioxidants | ICU Acquired Infection | Microbiological Confirmed | 87 participants |
| Antioxidants | ICU Acquired Infection | Infections classified as 'definite' or 'probable' | 120 participants |
| Glutamine + Antioxidants | ICU Acquired Infection | Infections classified as 'definite' or 'probable' | 110 participants |
| Glutamine + Antioxidants | ICU Acquired Infection | All Infections | 168 participants |
| Glutamine + Antioxidants | ICU Acquired Infection | Microbiological Confirmed | 83 participants |
| Placebo | ICU Acquired Infection | All Infections | 181 participants |
| Placebo | ICU Acquired Infection | Microbiological Confirmed | 96 participants |
| Placebo | ICU Acquired Infection | Infections classified as 'definite' or 'probable' | 128 participants |
Secondary
ICU Length of Stay
Measure of the duration of participant stay in the ICU
Time frame: Day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glutamine | ICU Length of Stay | 8.9 days |
| Antioxidants | ICU Length of Stay | 8.9 days |
| Glutamine + Antioxidants | ICU Length of Stay | 8.9 days |
| Placebo | ICU Length of Stay | 8.3 days |