Rationale and design of a mechanistic clinical trial of JAK inhibition to prevent ventilator-induced diaphragm dysfunction. (November 2021)

• Record Type: Journal Article
• Authors: Shrager, Joseph B.; Wang, Yoyo; Lee, Myung; Nesbit, Shannon; Trope, Winston; Konsker, Harrison; Fatodu, Emmanuel; Berry, Mark S.; Poulstides, George; Norton, Jeffrey; Burdon, Thomas; Backhus, Leah; Cooke, Roger; Tang, Huibin
• Is Part Of: Respiratory medicine. Volume 189(2021)
• Publication Date: 2021-11
• Subjects: Positive pressure respiration -- Ventilator weaning -- Muscle weakness -- Muscular atrophy -- Respiration, artificial -- Respiration; Chest -- Diseases -- Periodicals; Chest -- Diseases -- Great Britain -- Periodicals; Respiratory organs -- Diseases -- Periodicals; Respiratory Tract Diseases -- Periodicals; Appareil respiratoire -- Maladies -- Périodiques; Thorax -- Maladies -- Périodiques; Appareil respiratoire -- Maladies -- Traitement -- Périodiques; Electronic journals; 616.2
• DOI: 10.1016/j.rmed.2021.106620
• Languages: English
• ISSNs: 0954-6111

Abstract

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. Highlights: Diaphragm weakness prolongs MV in many ventilated patients, impacting outcomes. There is no current drug therapy for this important problem. Inhibition of the JAK/STAT pathway prevents diaphragm weakness in ventilated rats. We describe an ongoing clinical trial of JAK inhibition (Tofacitinib) in ventilated patients. Outcome measures will be single fiber diaphragm force studies and molecular. Abstract : Trial is registered at Clinicaltrials.gov # NCT03681275.