Potential Diaphragm Muscle Weakness-related Dyspnea Persists 2 Years after COVID-19 and Could Be Improved by Inspiratory Muscle Training: Results of an Observational and an Interventional Clinical Trial

Abstract

Rationale: Diaphragm muscle weakness might underlie persistent exertional dyspnea, despite normal lung and cardiac function in individuals who were previously hospitalized for acute coronavirus disease (COVID-19) illness. Objectives: The authors sought, first, to determine the persistence and pathophysiological nature of diaphragm muscle weakness and its association with exertional dyspnea 2 years after hospitalization for COVID-19 and, second, to investigate the impact of inspiratory muscle training (IMT) on diaphragm and inspiratory muscle weakness and exertional dyspnea in individuals with long COVID. Methods: Approximately 2 years after hospitalization for COVID-19, 30 individuals (11 women, 19 men; median age, 58 years; interquartile range [IQR] = 51-63) underwent comprehensive (invasive) respiratory muscle assessment and evaluation of dyspnea. Eighteen with persistent diaphragm muscle weakness and exertional dyspnea were randomized to 6 weeks of IMT or sham training; assessments were repeated immediately after and 6 weeks after IMT completion. The primary endpoint was change in inspiratory muscle fatiguability immediately after IMT. Measurements and Main Results: At a median of 31 months (IQR = 23-32) after hospitalization, 21 of 30 individuals reported relevant persistent exertional dyspnea. Diaphragm muscle weakness on exertion and reduced diaphragm cortical activation were potentially related to exertional dyspnea. Compared with sham control, IMT improved diaphragm and inspiratory muscle function (sniff transdiaphragmatic pressure, 83 cm H₂O [IQR = 75-91] vs. 100 cm H₂O [IQR = 81-113], P = 0.02), inspiratory muscle fatiguability (time to task failure, 365 s [IQR = 284-701] vs. 983 s [IQR = 551-1,494], P = 0.05), diaphragm voluntary activation index (79% [IQR = 63-92] vs. 89% [IQR = 75-94], P = 0.03), and dyspnea (Borg score, 7 [IQR = 5.5-8] vs. 6 [IQR = 4-7], P = 0.03). Improvements persisted for 6 weeks after IMT completion. Conclusions: To the best of the authors' knowledge, this study is the first to identify a potential treatment for persisting exertional dyspnea in long COVID and provide a possible pathophysiological explanation for the treatment benefit. Clinical trial registered with www.clinicaltrials.gov (NCT04854863, NCT05582642).

Keywords: coronavirus; diaphragm muscle strength; exertional dyspnea; inspiratory muscle strength training; pulmonary function.

Figure 1.

CONSORT flow diagram. IMT = inspiratory muscle training.

Figure 2.

Experimental setup. (A) Subject with transnasal placement of double-balloon catheter measuring pressure from esophageal and gastric sensors for the calculation of transdiaphragmatic pressure (Pdi); magnetic coil placement for delivery of cervical magnetic stimulation (CMS) and 10th thoracic vertebrae (TH10) is shown for assessment of inspiratory and expiratory muscle strength, respectively. (B) Curves during different voluntary and nonvoluntary maneuvers. Readings from esophageal pressure (Pes) and gastric pressure (Pgas) sensors and calculated Pdi are shown. Representative twitch pressure recording after CMS and further in-depth analysis of a twitch curve; pressure amplitude, duration of the pressure deflection, maximum rate of contraction (MRC), and maximum rate of relaxation (MRR) were analyzed. MRC is defined as the positive peak of the pressure derivative as a function of time (i.e., the steepest slope of the inclining twitch Pdi [twPdi] curve) and reflects the maximum velocity of diaphragm contraction. MRR is defined as the negative peak of the pressure derivative over time and measures the initial part of the pressure decay, reflecting the maximum velocity of muscle relaxation. Both MRC and MRR were adjusted for twPdi. CMS twitches are superimposed on voluntary contraction and voluntary Pdi; performed on Mueller maneuver (negative Pes and positive Pgas). The diaphragm voluntary activation index (DVAI) reflects the percentage of diaphragmatic muscle mass activated by voluntary effort or the extent of diaphragmatic activation during any given inspiratory effort. *Means that (following the arrow) a zoomed in version of this part is provided here. (C) Placement of electromyogram (EMG) electrodes and ultrasound probe on both hemi diaphragms, parasternal intercostal and sternocleidomastoid muscle. (D) Raw EMG muscle signals with their respective root-mean-square (RMS) channel. (E) Representative examples of diaphragm (left) and parasternal intercostal (right) muscle ultrasound in inspiration (top) and expiration (bottom).

Figure 3.

Key study findings in the treatment (red) and sham (green) arms. *Significant between-groups differences (P < 0.05). (A) The impact of inspiratory muscle training (IMT) on exertional dyspnea. (B and C) Effects of IMT on endurance time, volitional and nonvolitional respiratory muscle parameters, 6MWD, and pulmonary function parameters. (D) Change in sniff nasal pressure and training parameters during 6 weeks of IMT. 6MWD = 6-minute walk distance; Borg = Borg dyspnea scale score; CRQ Dyspnea = Chronic Respiratory Questionnaire dyspnea domain score; DVAI = diaphragm voluntary activation index; mMRC = modified Medical Research Council dyspnea scale score; Pdi = diaphragmatic pressure; Pgas = gastric pressure; SNIP = sniff nasal inspiratory pressure; tw = twitch; VC = vital capacity.