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.

中文翻译：

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JAK抑制剂预防呼吸机引起的膈肌功能障碍的机械临床试验的原理和设计

介绍

呼吸机引起的膈肌功能障碍 (VIDD) 是一种重要现象，已在机械通气的实验和临床模型中反复证明。即使是几个小时的 MV 也会启动信号级联反应，首先导致比力降低，然后是膈肌纤维萎缩。这种严重的、进行性的关键通气肌无力导致 MV 持续时间增加，从而增加了 MV 相关并发症/死亡。一种可以预防 VIDD 的药物可能会对重症监护病房的结果产生重大的积极影响。我们确定 JAK/STAT 通路在 VIDD 中很重要，然后证明 JAK 抑制可以防止大鼠的 VIDD。

材料和方法

已启动的 NIH 资助的临床试验是一项前瞻性、安慰剂对照试验：接受食管切除术的受试者随机接受 6 个术前剂量的 FDA 批准的 JAK 抑制剂 Tofacitinib（常用于类风湿性关节炎）与安慰剂。主要结果变量将是在 6 小时 MV 中，托法替尼与安慰剂受试者中横膈单肌纤维的力产生（标准化为其横截面积）的差异。

讨论

该试验代表了预防 VIDD 药物的首次人体机械临床试验。它将在人类受试者中提供 JAK 抑制是否可以预防临床 VIDD 的概念验证，如果成功，将支持基于 ICU 的临床试验，该试验将确定 JAK 抑制是否影响临床结果变量，例如 MV 持续时间和死亡率。