Weakness is a major complication of critical illness that complicates recovery both during the first few weeks following illness as well as the quality of life 1 to 2 years after the illness. During the acute recovery period, weakness often prevents patient weaning from the ventilator, prolonging intensive care unit stays, and leading to greatly increased cost, complication rates and mortality. In a recently published paper we found, in both patients and rats, that difficulty in recruitment of motoneurons to fire is an important contributo to weakness triggered by critical illness. Preliminary data presented in this grant suggests difficulty recruiting motoneurons to fire may persist after recovery from critical illness and thus may contribute to long term weakness. Reduced motoneuron excitability as a mechanism of weakness has never been proposed and thus represents a novel area of research into weakness triggered by critical illness. In vivo intracellular recording from motoneurons in adult rats will be used in combination with modeling of motoneuron excitability to identify potential mechanisms underlying the reduction of excitability. Potential mechanisms will further be explored using dynamic clamp of motoneurons in vivo to correct the defect(s) in ion channels that underlie the reduction in excitability. Preliminary data suggests we have identified a class o drugs that can correct the defect in excitability. It is our hope that identification of drugs that improve motoneuron excitability will rapidly translate to new therapy that improves the rate of rehabilitation and the quality of life for patients after hospital discharge.

Public Health Relevance

Our work will be the first to determine the mechanism underlying a previously unsuspected contributor to weakness in critically ill patients: reduced motoneuron excitability. If successful we will develop novel therapy to promote recovery of strength following critical illness. By promoting recovery we hope to greatly reduce complication rates to improve outcome and quality of life after hospital discharge.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS082354-01A1
Application #
8760655
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wright State University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Dayton
State
OH
Country
United States
Zip Code
45435
Novak, Kevin R; Norman, Jennifer; Mitchell, Jacob R et al. (2015) Sodium channel slow inactivation as a therapeutic target for myotonia congenita. Ann Neurol 77:320-32