Safety and Dose Escalation Study of Zinc Supplementation in Critically Ill Children

Study Overview
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Brief Summary
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The purpose of the study is 1) to determine whether administration of intravenous zinc to critically ill children is safe, and 2) to determine an appropriate dose of zinc supplementation.

Detailed Description
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Our recently published studies in children with septic shock demonstrated that pediatric septic shock is characterized by large scale repression of genes that either directly depend on normal zinc homeostasis or directly participate in zinc homeostasis. Functional validation studies demonstrated that nonsurvivors of pediatric septic shock have abnormally low serum zinc concentrations. A follow-up pilot study in a general population of critically ill children demonstrated that the presence of low plasma zinc concentrations is a prevalent problem in critically ill children. In addition, low plasma zinc concentrations correlate inversely with indices of inflammation and directly with the number of organ failures. These preliminary data, coupled with the expected safety of zinc supplementation, provided the rationale for a double blinded, prospective, placebo-controlled trial of zinc supplementation in critically ill children, with the two primary study endpoints to assess efficacy being highly clinically relevant: reduction of the lymphopenia rate and improvement of glucose homeostasis. Although the proposal was well-received, the primary concern precluding funding of this trial were lack of safety and dosing data for intravenous zinc. We have therefore developed a proposal for a Phase I/II study of safety and pharmacokinetics to address these concerns. It is anticipated that data generated through this proposal will provide the necessary preliminary data to re-submit our application for an interventional efficacy trial of zinc supplementation in critically ill children

Official Title
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A Safety and Dose-escalation Study of Zinc Supplementation in Pediatric Critical Illness

Conditions
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Critical Illness

Intervention / Treatment
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* Drug: Zinc sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admission to pediatric intensive care unit Age between 1 month and 10 years Pediatric Risk of Mortality III score > 5, OR presence of at least 1 new organ failure Anticipated pediatric intensive care unit length of stay > 3 days Ability of parent or legal guardian to provide informed consent Exclusion Criteria: Known zinc deficiency Pre-existing bone marrow failure New or existing diagnosis of diabetes mellitus Limitation of care orders in place New diagnosis of brain injury, encephalopathy Clinical contraindication for zinc supplementation

Ages Eligible for Study
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Minimum Age: 30 Days
Maximum Age: 10 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: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group<br>No intervention | |
| Active Comparator: Low dose group<br>250 mcg/kg/day supplemental IV zinc sulfate divided every 8 hours for 7 days | Drug: Zinc sulfate<br>* Zinc sulfate 200 mcg/ml in Normal Saline<br>|
| Active Comparator: Medium dose group<br>500 mcg/kg/day supplemental IV zinc sulfate q8 hours for 7 days | Drug: Zinc sulfate<br>* Zinc sulfate 200 mcg/ml in Normal Saline<br>|
| Active Comparator: High dose group<br>750 mcg/kg/day supplemental IV zinc sulfate q8 hrs for 7 days | Drug: Zinc sulfate<br>* Zinc sulfate 200 mcg/ml in Normal Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Zinc Concentration Over Time | Plasma Zinc levels were measured daily during the seven day study period in each group. | 7 days | 
| New Fever | Because of reports of fever in patients wiht zinc overdoses, we monitored patients for new fever while on supplementation | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose Homeostasis | Patients were assigned a score based on glucose range to take into account the degree of hyperglycemia as well as the need for insulin over the course of the 7 day study period. This score is an ordinal scale ranging from 1 to 5, with a score of 1 indicating no hyperglycemia, and 5 indicating severe hyperglycemia despite insulin administration. | 7 days |