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

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

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.

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

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