Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction

Abstract

Introduction: Ventilator-induced diaphragm dysfunction (VIDD) is an important phenomenon that has been repeatedly demonstrated in experimental and clinical models of mechanical ventilation. Even a few hours of MV initiates signaling cascades that result in, first, reduced specific force, and later, atrophy of diaphragm muscle fibers. This severe, progressive weakness of the critical ventilatory muscle results in increased duration of MV and thus increased MV-associated complications/deaths. A drug that could prevent VIDD would likely have a major positive impact on intensive care unit outcomes. We identified the JAK/STAT pathway as important in VIDD and then demonstrated that JAK inhibition prevents VIDD in rats. We subsequently developed a clinical model of VIDD demonstrating reduced contractile force of isolated diaphragm fibers harvested after ∼7 vs ∼1 h of MV during a thoracic surgical procedure.

Materials and methods: The NIH-funded clinical trial that has been initiated is a prospective, placebo controlled trial: subjects undergoing esophagectomy are randomized to receive 6 preoperative doses of the FDA-approved JAK inhibitor Tofacitinib (commonly used for rheumatoid arthritis) vs. placebo. The primary outcome variable will be the difference in the reduction that occurs in force generation of diaphragm single muscle fibers (normalized to their cross-sectional area), in the Tofacitinib vs. placebo subjects, over 6 h of MV.

Discussion: This trial represents a first-in-human, mechanistic clinical trial of a drug to prevent VIDD. It will provide proof-of-concept in human subjects whether JAK inhibition prevents clinical VIDD, and if successful, will support an ICU-based clinical trial that would determine whether JAK inhibition impacts clinical outcome variables such as duration of MV and mortality.

Keywords: Muscle weakness; Muscular atrophy; Positive pressure respiration; Respiration; Respiration, artificial; Ventilator weaning.

Conflict of interest statement

Conflict of Interest Statement

None of the authors have any conflicts of interest relevant to the subject of this study/manuscript.

Published by Elsevier Ltd.

Figures

Figure 1.

JAK inhibition prevents the reduction of muscle-specific diaphragm force that occurs in mechanically ventilated rats. A) MV induces STAT3 phosphorylation and JAK inhibitor R545 blocks this activation. Control and MV (18 h) rat diaphragm muscles were subjected to Western blot analysis (n=4 rats per group). B) Treatment with JAK inhibitor prevents MV-induced contractile dysfunction. Force frequency relationship from stimulated, ex-vivo diaphragm strips from controls (n=10) and MV rats treated with JAK inhibitor (n=8) or vehicle (n=9) (adapted from ref 27).

Figure 2.

Human diaphragm muscle fibers, similar to rat, demonstrate activation/phosphorylation of STAT3 after 7 hours of mechanical ventilation. A) Western blots from 5 representative subjects demonstrate similar STAT3 levels at 1 and 7 h, but increased pSTAT3 at 7 h. B) The pSTAT3 to STAT3 ratio is significantly elevated at 7 h vs. 1 h (n=14, *p=0.032)

Figure 3.

Maximal force generation of isolated, skinned single human diaphragm fibers is reduced at 7 h MV vs. 1 h MV (p=0.024). Each point represents a single fiber, with bars showing the range of forces measured. n=39 fibers from 6 subjects. See text for detailed methods.

Figure 4.

Study timeline: includes drug administration schedule, surgery and diaphragm/serratus biopsies, and follow-up.

Figure 5.

Schematic of the clinical model used for the trial. Diaphragm and Serratus Anterior biopsies are harvested after 1 hour and 7 hours of mechanical ventilation while the patient/subject undergoes an esophagectomy. The diaphragm fibers (and control serratus muscle fibers) are studied for changes in STAT3 activation and for the development of diaphragm weakness in ex vivo study of single, isolated, skinned muscle fibers.