Zinc Therapy in Critical Illness

Sepsis is a clinical syndrome often caused by a bloodstream infection that results in a
common set of symptoms termed systemic inflammatory response syndrome (SIRS). Severe sepsis
(sepsis with organ failure) is the leading cause of death in critically ill patients in the
US. Most patients with severe sepsis need to be treated in the intensive care unit with
mechanical ventilation and intravenous antibiotics. Between 30 to 50% of all severe sepsis
patients die and quality of life in survivors is substantially reduced. New therapies are
needed to improve clinical outcomes in patients with sepsis.

A new area of interest in the treatment of critical illness is pharmaconutrition, in which
micronutrients (like zinc) are studied and administered to determine if they affect the
inflammatory response or immunologic processes in critical illness. The FDA does not regulate
micronutrients and does not require rigorous pharmacokinetic (the study of how a drug or
nutrient is metabolized in the body) testing so it is not clear how to dose micronutrients in
critically ill patients. It is also not clear if critically ill patients would metabolize
these micronutrients differently than healthy people and would need different dosing levels.
This is true of zinc, the focus of this research study.

Zinc is essential for normal immune function, oxidative stress response, and wound healing,
and its homeostasis is tightly regulated. Zinc deficiency occurs in >10% of Americans and
leads to loss of innate and adaptive immunity and increased susceptibility to infections. The
symptoms of zinc deficiency are similar to many of the symptoms of SIRS and there is strong
biologic rationale to suggest that the zinc deficiency seen in nearly all sepsis patients may
contribute to the development of sepsis syndrome and to the "immunoparalysis" common in
sepsis patients

This study has three specific aims, 1) to perform a phase I dose-finding study of intravenous
zinc in mechanically ventilated patients with severe sepsis; 2) to define the pharmacokinetic
of intravenous zinc in mechanically ventilated patients with severe sepsis compared to
healthy controls; and 3) to investigate the impact of zinc on inflammation, immunity, and
oxidant defense in patients with severe sepsis.

A total of 40 critically ill patients from the FAHC intensive care units and 15 healthy
controls will be enrolled in the study. The critically ill patient population will be divided
into 4 dosing groups of 10 subjects (7 randomized to zinc and 3 to saline placebo). Group 1
will receive 500mcg/kg IBW/day elemental zinc in divided doses every 8 hours. If the 50th
percentile of the normal plasma zinc range (110mcg/dL) has not been achieved in all patients
by 7 days and there are no safety concerns, sequential groups of patients will receive
increasing doses in 250mcg increments to the ceiling dose. Groups 2 through 4 will receive
750, 1000, and 1250mcg/kgIBW/day elemental zinc, respectively. Each participant will receive
the intravenous zinc or placebo for a total of 7 days unless they die or leave the ICU
earlier. Pharmacokinetic testing will be obtained from 40 of the critically ill subjects and
in 15 healthy controls. Additional blood will be drawn during the infusion protocol to
investigate the impact of zinc on inflammation, immunity, and oxidant defense.