Sepsis is a common and devastating disease and the leading cause of death in critically ill patients. Microcirculatory failure is a pivotal pathogenic event in sepsis that can play a major role in sepsis-associated organ dysfunction. Our group and others have used orthogonal polarization spectral videomicroscopy, anon- invasive technique of measuring microcirculatory flow indices in human subjects, to demonstrate that impaired microcirculatory flow in sepsis is associated with multi-organ failure and mortality. Currently, there are no novel therapies for sepsis that specifically target the microcirculation. Nitric oxide (NO) maintains microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult as it does in sepsis. Although NO is globally upregulated in sepsis, NO production is heterogeneous between and within organ systems at the microcirculatory level, and some microcirculatory units have low flow. Inhaled nitric oxide (iNO) can deliver NO effectively to the systemic microcirculation and "open" these low-flow microcirculatory units. We hypothesize that iNO will augment microcirculatory perfusion during sepsis resuscitation with early goal-directed therapy (EGDT), and this increase in microcirculatory flow will result in more effective resuscitation and decreased organ failure.
We aim to test this hypothesis with a randomized double-blind placebo-controlled trial to evaluate the ability of iNO to (1) augment microcirculatory perfusion indices during EGDT;and (2) improve two clinically important outcome measures: (a) lactate clearance during EGDT, and (b) the Sequential Organ Failure Assessment score at 24 hours. The overall purpose of this Mentored Patient-Oriented Research Career Development Award is not only to deliver a successful investigation, but more importantly, a successful investigator. The PI's ultimate goal is to develop into an independent investigator who conducts important and innovative clinical trials in patients with circulatory shock. This mentored research training experience will consist of a five-year curriculum specifically focused on clinical trials training. There will be three distinct elements: 1) mentoring, 2) didactic education, and 3) investigation. The mentoring team features a number of renowned experts in sepsis research, including a primary mentor who has conducted NIH-funded research on the microvascular response to sepsis. The PI will train in a rigorous didactic program (Masters of Science in Clinical Epidemiology) and receive formal preparation in the design and analysis of clinical trials. Ultimately, this mentored experience will produce a PI who competes for independent research grants from the NIH. This project will be the first randomized trial specifically targeting the microcirculation in sepsis patients. Given the persistently high morbidity and mortality of sepsis (215,000 deaths annually in the U.S.), this type of clinical trial that uses novel methods to evaluate and treat sepsis has the potential to impact numerous lives and substantially benefit public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23GM083211-05
Application #
8260197
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$115,331
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Massey, Michael J; Larochelle, Ethan; Najarro, Gabriel et al. (2013) The microcirculation image quality score: development and preliminary evaluation of a proposed approach to grading quality of image acquisition for bedside videomicroscopy. J Crit Care 28:913-7
Skibsted, Simon; Arnold, Ryan; Sherwin, Robert et al. (2013) The association of near infrared spectroscopy-derived StO2 measurements and biomarkers of endothelial activation in sepsis. Intern Emerg Med 8:529-36
Skibsted, Simon; Jones, Alan E; Puskarich, Michael A et al. (2013) Biomarkers of endothelial cell activation in early sepsis. Shock 39:427-32
Puskarich, Michael A; Trzeciak, Stephen; Shapiro, Nathan I et al. (2013) Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. Chest 143:1548-53
Puskarich, Michael A; Trzeciak, Stephen; Shapiro, Nathan I et al. (2011) Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med 39:2066-71
Kilgannon, J Hope; Jones, Alan E; Parrillo, Joseph E et al. (2011) Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest. Circulation 123:2717-22
Puskarich, Michael A; Trzeciak, Stephen; Shapiro, Nathan I et al. (2011) Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock. Resuscitation 82:1289-93
Jones, Alan E; Shapiro, Nathan I; Trzeciak, Stephen et al. (2010) Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 303:739-46
Kilgannon, J Hope; Jones, Alan E; Shapiro, Nathan I et al. (2010) Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 303:2165-71
Shapiro, Nathan I; Schuetz, Philipp; Yano, Kiichiro et al. (2010) The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care 14:R182

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