Terminated for futility on 11/30/09 based on the recommendation of the DSMB

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.

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.

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

Adverse events were collected for 28 days.

For adverse events, denominators reflect Safety Population of those patients receiving each treatment. Therefore, denominators are 148 patients receiving Daily Nutriceutical Supplementation and 139 patients receiving Whey Protein.

The Data Safety Monitoring Board met on November 30, 2009. Interim analysis of the first 273 patients was presented. Per the Board's recommendations, the study was terminated based on futility.