More humans die in the intensive care unit from sepsis than from any other cause. Death from sepsis is the culmination of widespread hypoperfusion, cellular hypoxia, and multiple organ failure. A growing body of evidence shows that early therapeutic intervention improves outcomes for patients with sepsis. Novel targeted strategies that bolster a strong and durable systemic hemodynamic response have been proven to reduce or even reverse organ dysfunction in patients with sepsis. L-carnitine provides the key elements of a novel therapy to ameliorate the adverse hemodynamic effects of sepsis. Severe physiological stress forces energy metabolism to shift from primary fatty acid oxidation toward glycolysis and lactate oxidation. Prior work has shown that exogenous L-carnitine administration enhances glucose and lactate oxidation, attenuates fatty acid toxicity, and improves endothelial-smooth muscle coupling and cardiac mechanical efficiency. The overall goal of this proposal is to investigate L-carnitine as a novel adjunctive treatment of septic shock. In this study we will test our primary hypothesis: Early adjunctive L-carnitine administration in vasopressor dependent septic shock will significantly reduce cumulative organ failure at 48 hours with an associated decrease in 28-day mortality suggesting the need for further phase III study. To accomplish this we will conduct a phase II, double blinded, placebo controlled, adaptive randomized trial of 250 eligible patients with vasopressor-dependent septic shock. Study subjects will be assigned to one of four arms: low (6g), medium (12g) or high (18g) dose intravenous L-carnitine or placebo for 12 hours as a part of early resuscitative care. Our first ai is to assess whether L-carnitine reduces cumulative organ failure in patients with septic shock. The first efficacy endpoint of the trial is reduction in cumulative organ failure, defined as a decrease in the sequential organ failure assessment (SOFA) score at 48 hours after treatment. The SOFA data will be used to preferentially allocate subsequent patients to the L-carnitine dose that is most effective. As the trial progresses 28-day mortality data will be used to determine the probability that the dose of L-carnitine associated with the largest decrease in SOFA score would demonstrate efficacy in a subsequent phase III trial. By utilizing the strengths of an adaptive trial approach we can overcome several inefficiencies associated with traditional trials while maintaining protection against false positive results, and allow for dose finding, all while maintaining a manageable sample size.
Our second aim i s to assess if L-carnitine improves blood flow in the sublingual microvasculature during septic shock. We will use sidestream dark-field video-microscopy imaging of the sublingual microcirculation to directly visualize microcirculatory flow and to determine the effect of L-carnitine and placebo treatment on change in flow. Presently there are no treatments that are specific for targeting attenuation or reversal of organ dysfunction in sepsis. If this project shows benefit with L-carnitine, it will provide a useful, inexpensive, and widely applicable agent to the armamentarium of sepsis therapeutics.

Public Health Relevance

The relevance of this project to public health lies in its potential ability to provide a novel, inexpensive and widely generalizable therapy for septic shock that is targeted at organ dysfunction. If proven useful, this therapy could hasten recovery from septic shock and result in saving thousands of lives per year from this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM103799-02
Application #
8478149
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$545,466
Indirect Cost
$105,561
Name
University of Mississippi Medical Center
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216