Clinical trial NCT01162109: Zinc Therapy in Critical Illness
Official title: Pharmaconutrients as Therapies for Critical Illness: Zinc in Severe Sepsis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Severe Sepsis
Keywords: Zinc
sepsis
critical illness
mechanical ventilation
ICU
Lead sponsor: University of Vermont
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2010-07-14
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Severe sepsis
* Requiring mechanical ventilation
* 18 years or older

Exclusion Criteria:

* \>36 hours since meeting severe sepsis criteria4
* Expected ICU length of stay \<72 hours
* Pre-existing gastrointestinal disease\*
* Post-cardiac arrest with significant anoxic brain injury
* Creatinine clearance \<40mL/min\*
* Taking zinc supplement during past month\*
* Has received zinc supplementation while hospitalized
* Pregnant or lactating\*
* AIDS with CD4\<200\*
* Previous bone marrow or solid organ transplant\*
* Receiving TPN with added zinc

Primary outcomes:
measure: Pharmacokinetics/pharmacodynamics
timeFrame: Several time points over one week during critical illness
Secondary outcomes:
measure: Production of TNF-alpha by circulating monocytes
timeFrame: Study days 1, 3, and 7
measure: Production of IL-1beta by circulating monocytes
timeFrame: Study days 1, 3, and 7
measure: Production of IL-6 by circulating monocytes
timeFrame: Study days 1, 3, and 7
measure: Production of IL-8 by circulating monocytes
timeFrame: Study days 1, 3, and 7
measure: Plasma TNF-alpha
timeFrame: Study days 1, 3, and 7
measure: Plasma IL-1beta
timeFrame: Study days 1, 3, and 7
measure: Plasma IL-6
timeFrame: Study days 1, 3, and 7
measure: Plasma IL-8
timeFrame: Study days 1, 3, and 7
measure: Serum malondialdehyde (MDA)
timeFrame: Study days 1, 3, and 7
measure: Serum 8-hydroxydeoxyguanine (8-OHdG)
timeFrame: Study days 1, 3, and 7
measure: Neutrophil phagocytosis
timeFrame: Study days 1, 3, and 7
Other outcomes:
Locations:
city: Burlington
country: United States
facility: University of Vermont College of Medicine
state: Vermont
Study officials:
affiliation: University of Vermont
name: Renee D Stapleton, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: