Sepsis
Conditions
Keywords
sepsis, prevention, mineral supplementation
Brief summary
Despite strict hand washing, sterile technique, and antibiotic-coated catheters, nosocomial infection and sepsis remain the leading acquired causes of morbidity and mortality in critically ill children. Subsequent use of antibiotics to treat nosocomial infection and sepsis is considered a major attributable factor in the rise of antibiotic-resistant organisms in this population of children. This study will use a double-blind, randomized, controlled trial design to test the hypothesis that daily prophylaxis with metoclopramide, zinc, selenium and glutamine will reduce nosocomial infection and sepsis in critically ill children.
Detailed description
Despite strict hand washing, sterile technique, and antibiotic-coated catheters, nosocomial infection and sepsis remain the leading acquired causes of morbidity and mortality in critically ill children. Subsequent use of antibiotics to treat nosocomial infection and sepsis is considered a major attributable factor in the rise of antibiotic-resistant organisms in this population of children. Presently, prophylaxis strategies are used to prevent stress-induced gastrointestinal bleeding; however, no prophylaxis strategy is used to prevent stress-induced nosocomial infection and sepsis. When left unopposed, the stress hormone, cortisol, induces lymphocyte apoptosis, lymphopenia, and immune insufficiency. Prolactin is the counter-regulatory stress hormone that prevents cortisol-induced apoptosis and immunosuppression. Zinc, selenium, and glutamine are also important in maintenance of lymphocyte health. Critically ill patients commonly develop hypoprolactinemia secondary to increased central nervous system dopaminergic activity, as well as zinc, selenium, and glutamine deficiency caused by increased utilization and decreased supply. Hypoprolactinemia can be prevented by metoclopramide, a dopamine 2 receptor antagonist commonly used as a prokinetic in children, and zinc, selenium, and glutamine deficiency can be prevented with enteral supplementation. This study will use a double-blind randomized controlled trial design to test the hypothesis that daily prophylaxis with metoclopramide, zinc, selenium and glutamine will reduce nosocomial infection and sepsis in critically ill children.
Interventions
DRUGMetoclopramide
0.2 mg/kg/dose IV every 12 hours
DRUGZinc
one enteral dose daily of zinc chloride (10 mg/day elemental zinc for infants \< or equal to one year of age, and 20 mg/day elemental zinc for patients \> 1 year of age)
DIETARY_SUPPLEMENTGlutamine
one enteral dose daily of glutamine 0.3 gm/kg/day
DRUGSelenium
one enteral dose daily of selenium (40 μg for infants \< 8 months of age, 60 μg for infants 8 to 12 months of age, 90 μg for children 1-3 years, 150 μg for children 4-8 years, 280 μg for children 9 to 13 years, and 400 μg for children \> 13 years)
OTHERsaline
equivalent volume of intravenous saline
OTHERsterile water
equivalent volume of sterile water
OTHERselenium
equivalent volume of sterile water
DIETARY_SUPPLEMENTwhey-protein
one enteral dose daily of whey-protein
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Seattle Children's Hospital
Children's Hospital Los Angeles
Arkansas Children's Hospital Research Institute
Children's Hospital of Michigan
University of Pittsburgh
Children's National Research Institute
University of California, Los Angeles
Harborview Injury Prevention and Research Center
Michael Dean
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
During the initial accrual period for this study, prior to the first interim analysis, patients will be eligible for enrollment if they: * are between 12 months and less than 18 years; AND * are within the first 48 hours of the PICU admission; AND * have an endotracheal tube, central venous catheter (new or old, tunneled or not tunneled), or Foley catheter; AND * are anticipated to have an indwelling arterial or central venous catheter for blood sampling during the first three days of study enrollment. After the Data Safety Monitoring Board (DSMB) conducts its first interim evaluation, after enrollment of approximately 200 subjects, a decision will be made by the DSMB concerning enrollment of subjects between 40 weeks gestational age and 12 months. If the DSMB approves enrollment of infants after the first interim analysis, then patients will be eligible for enrollment if they: * are between 40 weeks gestational age and less than 18 years; AND * are within the first 48 hours of the PICU admission; AND * have an endotracheal tube, central venous catheter (new or old, tunneled or not tunneled), or Foley catheter; AND * are anticipated to have an indwelling arterial or central venous catheter for blood sampling during the first three days of study enrollment.
Exclusion criteria
During the initial accrual period for this study, prior to the first interim analysis, patients will be ineligible for enrollment if ANY of the following is true or anticipated: * are less than 1 year age; OR * are greater than or equal to 18 years of age; OR * have a known allergy to metoclopramide; OR * planned removal of endotracheal tube, central venous catheter, AND Foley catheters, within 72 hours of study enrollment, OR * suspected intestinal obstruction, OR * intestinal surgery or bowel disruption, OR * chronic metoclopramide therapy prior to enrollment, OR * failure to enroll within 48 hours of PICU admission, OR * readmission to PICU in the previous 28 days, OR * previously enrolled in this study, OR * lack of commitment to aggressive intensive care therapies. After the Data Safety Monitoring Board (DSMB) conducts its first interim evaluation, after enrollment of approximately 200 subjects, a decision will be made by the DSMB concerning enrollment of subjects between 40 weeks gestational age and 12 months. If the DSMB approves enrollment of infants after the first interim analysis, then patients will be ineligible for enrollment if ANY of the following is true or anticipated: * are less than 40 weeks gestational age; OR * are greater than or equal to 18 years of age; OR * have a known allergy to metoclopramide; OR * planned removal of endotracheal tube, central venous catheter, AND Foley catheters, within 72 hours of study enrollment, OR * suspected intestinal obstruction
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Primary Endpoint of This Study is the Median Time Between Admission to the PICU and Occurrence of Nosocomial Infection or Clinical Sepsis in PICU Patients Who Have Endotracheal Tubes, Central Venous Catheters, or Urinary Catheters. | 48 hours after admission until 5 days after discharged from the PICU |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Nosocomial Infection or Clinical Sepsis Per 100 Study Days | 48 hours after PICU admission till discharge from PICU | — |
| Antibiotic-free Days | 48 hours after admission until PICU discharge | — |
| Incidence of Prolonged Lymphopenia (Absolute Lymphocyte Count Less Than or Equal to 1,000/mm³ for > or Equal to 7 Days) | from time of PICU admission till discharge from PICU | What is reported is the number of participants with counts qualifying as lymphopenia. |
| All-cause 28-day Mortality Rate. | 28 days after admission to the PICU | — |
Countries
United States
Participant flow
Recruitment details
Dates of recruitment period: April 2007 - November 2009; Location: Pediatric Intensive Care Unit (PICU)
Pre-assignment details
Patients were stratified according to immunocompromised status prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Daily Nutriceutical Supplementation Subjects assigned to this group received zinc (20 mg), selenium (40 mcg ages 1-3 yrs, 100 mcg age 3-5 yrs, 200 mcg age 5-12 yrs, 400 mcg adolescent), and glutamine (0.3 g/kg) each morning, and intravenous metoclopramide (0.2 mg/kg, maximum 10 mg) every 12 hrs. | 149 |
| Whey Protein Subjects assigned to the whey protein group received 0.3 g/kg beneprotein each morning and intravenous saline every 12 hrs. | 144 |
| Total | 293 |
Baseline characteristics
| Characteristic | Daily Nutriceutical Supplementation | Whey Protein | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 149 Participants | 144 Participants | 293 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 7.9 years STANDARD_DEVIATION 5.6 | 8.4 years STANDARD_DEVIATION 5.9 | 8.1 years STANDARD_DEVIATION 5.7 |
| Immune Compromised at Study Entry Immune Competent | 135 Participants | 133 Participants | 268 Participants |
| Immune Compromised at Study Entry Immune compromised | 14 Participants | 11 Participants | 25 Participants |
| Region of Enrollment United States | 149 participants | 144 participants | 293 participants |
| Sex: Female, Male Female | 69 Participants | 79 Participants | 148 Participants |
| Sex: Female, Male Male | 80 Participants | 65 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 119 / 148 | 112 / 139 |
| serious Total, serious adverse events | 73 / 148 | 70 / 139 |
Outcome results
Primary
The Primary Endpoint of This Study is the Median Time Between Admission to the PICU and Occurrence of Nosocomial Infection or Clinical Sepsis in PICU Patients Who Have Endotracheal Tubes, Central Venous Catheters, or Urinary Catheters.
Time frame: 48 hours after admission until 5 days after discharged from the PICU
Population: Intention to treat analysis of all randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daily Nutriceutical Supplementation | The Primary Endpoint of This Study is the Median Time Between Admission to the PICU and Occurrence of Nosocomial Infection or Clinical Sepsis in PICU Patients Who Have Endotracheal Tubes, Central Venous Catheters, or Urinary Catheters. | 12.1 Days |
| Whey Protein | The Primary Endpoint of This Study is the Median Time Between Admission to the PICU and Occurrence of Nosocomial Infection or Clinical Sepsis in PICU Patients Who Have Endotracheal Tubes, Central Venous Catheters, or Urinary Catheters. | 13.2 Days |
Comparison: Null hypothesis was equal median time in both arms. Sample size calculated to yield 90% power to detect a significant effect, assuming inverse hazard rate of 1.5 using two-sided logrank test with alpha=0.05. This required recruitment until 263 patients with an event were enrolled (though the study was terminated early for futility by the DSMB).p-value: 0.29Log Rank
Secondary
All-cause 28-day Mortality Rate.
Time frame: 28 days after admission to the PICU
Population: This safety outcome was analyzed by treatment received, among a total of 284 children who received treatment and had known 28-day status.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daily Nutriceutical Supplementation | All-cause 28-day Mortality Rate. | 15 participants |
| Whey Protein | All-cause 28-day Mortality Rate. | 8 participants |
p-value: 0.16Chi-squared
Secondary
Antibiotic-free Days
Time frame: 48 hours after admission until PICU discharge
Population: All randomized patients per intention to treat analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daily Nutriceutical Supplementation | Antibiotic-free Days | 1 Days |
| Whey Protein | Antibiotic-free Days | 2 Days |
p-value: 0.09Wilcoxon (Mann-Whitney)
Secondary
Incidence of Prolonged Lymphopenia (Absolute Lymphocyte Count Less Than or Equal to 1,000/mm³ for > or Equal to 7 Days)
What is reported is the number of participants with counts qualifying as lymphopenia.
Time frame: from time of PICU admission till discharge from PICU
Population: All randomized patients (intention to treat analysis)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daily Nutriceutical Supplementation | Incidence of Prolonged Lymphopenia (Absolute Lymphocyte Count Less Than or Equal to 1,000/mm³ for > or Equal to 7 Days) | 5 participants |
| Whey Protein | Incidence of Prolonged Lymphopenia (Absolute Lymphocyte Count Less Than or Equal to 1,000/mm³ for > or Equal to 7 Days) | 12 participants |
p-value: 0.07Chi-squared
Secondary
Rate of Nosocomial Infection or Clinical Sepsis Per 100 Study Days
Time frame: 48 hours after PICU admission till discharge from PICU
Population: All randomized patients analyzed by intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Daily Nutriceutical Supplementation | Rate of Nosocomial Infection or Clinical Sepsis Per 100 Study Days | 4.99 Mean number of events per 100 study days |
| Whey Protein | Rate of Nosocomial Infection or Clinical Sepsis Per 100 Study Days | 4.83 Mean number of events per 100 study days |
Comparison: Null hypothesis of equal event rates in the two study arms.p-value: 0.81Rate analysis (see comments)