The CRISIS Prevention Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Critical Illness Stress-induced Immune Suppression Prevention Trial

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Metoclopramide
* Drug: Zinc
* Dietary Supplement: Glutamine
* Drug: Selenium
* Other: saline
* Other: sterile water
* Other: selenium
* Dietary Supplement: whey-protein


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zinc selenium glutamine metoclopramide<br>metoclopramide, zinc, selenium, and glutamine | Drug: Metoclopramide<br>* 0.2 mg/kg/dose IV every 12 hours<br>* Other names: Reglan;Drug: Zinc<br>* 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)<br>Dietary Supplement: Glutamine<br>* one enteral dose daily of glutamine 0.3 gm/kg/day<br>Drug: Selenium<br>* 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)<br>|
| Placebo Comparator: enteral whey protein and IV saline<br>saline, sterile water, whey protein | Other: saline<br>* equivalent volume of intravenous saline<br>Other: sterile water<br>* equivalent volume of sterile water<br>Other: selenium<br>* equivalent volume of sterile water<br>Dietary Supplement: whey-protein<br>* one enteral dose daily of whey-protein<br>* Other names: Beneprotein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | What is reported is the number of participants with counts qualifying as lymphopenia. | from time of PICU admission till discharge from PICU | 
| All-cause 28-day Mortality Rate. |  | 28 days after admission to the PICU | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, prevention, mineral supplementation