The goal of this project is to identify a drug that could be administered to patients who require mechanical ventilation (MV) in our intensive care units ? a drug which would reduce the time patients are required to be on the ventilator. It is known that MV leads to weakness of the diaphragm (ventilator-induced diaphragm dysfunction ? ?VIDD?). Since the diaphragm is the muscle that is primarily responsible for moving air into the lungs during breathing, if it becomes weak, then it becomes more difficult to separate patients from the ventilator. The resulting long-term dependence on the ventilator is associated with increased rates of complications and death. A drug that can be given at the initiation of MV and prevent weakness of the diaphragm will therefore reduce ventilator dependence and complications/deaths in intensive care unit (ICU) patients. Based upon work we have done previously, we know that inter-related molecules called ?JAK? and ?STAT3? are important in the etiology of VIDD in both animals and in humans. When we blocked the action of these molecules with a JAK inhibitor drug in mechanically ventilated animals, diaphragm weakness did not occur. We therefore believe that a JAK inhibitor holds promise as a drug to prevent VIDD in mechanically ventilated patients. We propose to study mechanically ventilated human subjects to determine if the FDA- approved JAK inhibitor, Tofacitinib, will prevent the activation of the biological processes that we know lead to VIDD and prevent VIDD itself. To achieve this, we will take 2 small diaphragm biopsies, 6 hours apart, in patients undergoing esophagectomy, and we will study the effects that MV and Tofacitinib have on the changes that occur in this tissue. Patients will be randomized to receiving Tofacitinib vs placebo prior to esophagectomy and diaphragm biopsies:
Aim 1 ?Study the biopsies to determine if JAK inhibition prevents the activation of JAK/STAT and known downstream effectors of VIDD in human diaphragm subjected to MV.
Aim 2 ?Study the biopsies to determine if JAK inhibition prevents the diaphragm weakness which defines VIDD in human diaphragm subjected to MV. This study will provide the required information to support a subsequent clinical trial in ICU patients, which we hope would establish that JAK inhibition will indeed reduce the duration of MV, complications, and deaths. It will also advance this field by allowing us to study pathways beyond JAK/STAT that may be important in causing VIDD in human diaphragm.
The proposed study will advance progress toward the identification of a drug which, if administered at the time of institution of mechanical ventilation, will reduce time on the ventilator, complications, and deaths among intensive care unit patients. Such a drug would also likely have a substantial impact on reducing the costs of care in patients requiring mechanical ventilation.
