This Award allows Dr. Stapleton to become an independent investigator performing translational research on nutrition and pharmaconutrients in critically ill patients with sepsis, a syndrome that is common in critical illness and has an enormous public health impact. Dr. Stapleton is trained in epidemiology, but to establish herself as an expert leader in nutrition and pharmaconutrient therapy in critical illness, she is seeking additional training in pharmacokinetics and translational research. Through a cohesive program of formal coursework, direct mentoring by outstanding experts, and practical experience conducting her proposed projects, this Award will help her achieve her career goals of translating novel nutrient interventions into clinical application. The overall objective of this proposal is to investigate the pharmacologic behavior and to perform a phase I dose-finding study of zinc in patients with severe sepsis. The biologic rationale for zinc in sepsis is strong. Zinc deficiency is present in nearly all critically ill patients and is associated with increased mortality and organ failure. Zinc supplementation in healthy volunteers restores normal immune function including normalizing lymphocyte count, decreasing inflammatory cytokine production, restoring phagocytic activity of neutrophils, and reducing incidence of infections. Supplementation also decreases organ failure and death in murine sepsis, and there is evidence from a few small clinical trials of antioxidant cocktails including zinc in critically ill humans that supplementation may improve survival.
Aim 1 is a phase I dose-finding study of intravenous zinc in patients with severe sepsis to identify a dose for use in future trials. The endpoints are normalization of plasma zinc level and safety and tolerability parameters including vomiting and diarrhea. The results of this study will lead to R01 or U01 applications for future clinical trials.
Aim 2 defines the pharmacokinetics of zinc in patients with severe sepsis compared to healthy controls and determines a dosing interval for zinc by investigating the hypothesis that the half-life of zinc in severe sepsis patients is significantly lower than in healthy controls.
Aim 3 investigates the impact of zinc on inflammation, immunity, and oxidant defense in patients with severe sepsis through selected laboratory measurements, work which will provide insight into biologic markers for use in future clinical trials. With the rich resources in translational research provided by the Vermont Lung Center, this is an exceptional opportunity for Dr. Stapleton to gain outstanding experience in pharmacokinetics, dose-finding studies, and translational research in critically ill patients with sepsis.

Public Health Relevance

Sepsis is a common syndrome in critical illness, has a tremendous public health impact, and new therapies are urgently needed. Zinc is a novel potential therapy, and this research is an innovative approach that establishes a new paradigm of investigating nutrient delivery to critically ill patients. It rigorously progresses through defining the pharmacokinetics and conducting a phase I dose-finding study, while investigating zinc's biologic impact using obtained blood samples, to obtain information that will inform the conduct of future clinical trials.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (M1))
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Sarkar, Rita
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University of Vermont & St Agric College
Internal Medicine/Medicine
Schools of Medicine
United States
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Esposito, Anthony J; Bhatraju, Pavan K; Stapleton, Renee D et al. (2017) Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome. Crit Care 21:304
Stapleton, Renee D; Benoit, Dominique D (2016) Does increased ICU strain prompt clinicians to communicate with families about end-of-life issues earlier? Intensive Care Med 42:1040-2
Mikacenic, Carmen; Hansen, Elizabeth E; Radella, Frank et al. (2016) Interleukin-17A Is Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome. Crit Care Med 44:496-502
Heyland, Daren K; Stapleton, Renee D; Mourtzakis, Marina et al. (2016) Combining nutrition and exercise to optimize survival and recovery from critical illness: Conceptual and methodological issues. Clin Nutr 35:1196-206
Ubags, Niki D J; Stapleton, Renee D; Vernooy, Juanita H J et al. (2016) Hyperleptinemia is associated with impaired pulmonary host defense. JCI Insight 1:
Manzanares, William; Dhaliwal, Rupinder; Jurewitsch, Brian et al. (2014) Parenteral fish oil lipid emulsions in the critically ill: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr 38:20-8
Stapleton, Renee D; Suratt, Benjamin T (2014) Obesity and nutrition in acute respiratory distress syndrome. Clin Chest Med 35:655-71
Shashaty, Michael G S; Stapleton, Renee D (2014) Physiological and management implications of obesity in critical illness. Ann Am Thorac Soc 11:1286-97
Manzanares, William; Dhaliwal, Rupinder; Jurewitsch, Brian et al. (2013) Alternative lipid emulsions in the critically ill: a systematic review of the evidence. Intensive Care Med 39:1683-94