Rehab and Mechanical Ventilation

Official title

Rehabilitation-based Approaches to Prevent Mechanical Ventilation-induced Breathing Dysfunction

Overview

The goal of this research study is to evaluate the effects of a single session of rehabilitation in healthy adults, before noninvasive mechanical ventilation (MV). MV can help support breathing function during sleep or illness. High levels of MV support have been reported to alter the function of the diaphragm muscle, the primary breathing muscle, in people with compromised health. However, rehabilitation may have some potential to improve diaphragm function in advance of using MV. This study will test different rehabilitation interventions, including (1) inspiratory strength training (IST), (2) transcutaneous spinal cord stimulation (TSCS), or sham TSCS. Before and after MV, participants will complete breathing strength tests and responses to phrenic nerve stimulation.

Detailed description

Brief periods of mechanical ventilation (MV) can degrade the function of the diaphragm, which can be a problem for older adults and people with multiple medical comorbidities. 20% of people who are placed on MV require a prolonged effort to wean back to independent breathing. The effects of MV on respiratory neural function are often unaddressed by typical clinical practices. Many aspects of clinical practice such as MV, anesthesia, opioid medication directly reduce respiratory neural drive and degrade diaphragm fiber contractile function, and these impairments can occur rapidly, persist after extubation, and increase the risk for postoperative pulmonary complications. These complications delay discharge, incur significant expenses, and place patients at risk for an incomplete recovery and significant morbidity. Thus, any rehabilitation strategies to preserve or improve phrenic/diaphragm motor function have the potential to expedite early post-operative mobilization and reduce the risk of complications.

Inspiratory muscle strength training (IST) is an effective rehabilitation method to strengthen the diaphragm muscle. Repetitive IST reinforces respiratory neuromuscular plasticity, induces diaphragm remodeling, and improves inspiratory strength. Bouts of high intensity inspiratory loading acutely increase respiratory neural drive and potentiates inspiratory motor recruitment. Additionally, in some clinical situations, IST exercise is not feasible, thus another option may be electrical stimulation of the diaphragm/phrenic motor area (C3-C6) to generate similar improvements in inspiratory drive to preserve breathing function.

The central hypothesis of this proposal is that rehabilitation to increase diaphragm excitability in advance of MV will offset post-MV inspiratory dysfunction. To test this hypothesis, a repeated-measures, blinded study of healthy adults without respiratory comorbidities will be recruited. Consenting participants will complete a familiarization session, followed by three separate, two-hour noninvasive MV sessions, one week apart. MV sessions will be preceded by: 1) a single, high-intensity IST session, and 2) transcutaneous spinal cord stimulation, and 3) sham electrical stimulation, in randomized order. Changes in respiratory drive, voluntary and evoked diaphragm strength, and dyspnea will be evaluated. The central hypothesis will be tested with the following aims:

Aim 1: Test the hypothesis that noninvasive, positive pressure ventilation acutely decreases respiratory drive and maximal diaphragm activation during a two-hour MV session and persists up to 24 hours later.

Aim 2: Test the hypothesis that even single rehabilitation sessions (IST, transcutaneous stimulation) in advance of MV will preserve evoked diaphragm recruitment and hasten early recovery from MV, when compared to sham stimulation.

Interventions

• Device Spinal cord stimulation
  Transcutaneous spinal cord stimulation at 2mA intensity, for 20 minutes.
• Behavioral Inspiratory Strength Training
  5 sets of 5 breaths of high-intensity inspiratory strength training
• Other Sham Stimulation
  Transcutaneous spinal cord stimulation at reduced intensity, lasting 1 minute at the beginning and end of a 20-minute session.

Primary outcome measures

• Maximal inspiratory pressure [Time frame: T1: baseline strength, T2: 2 hours after MV, T3: 24 hours after MV]
• Phrenic CMAP Response [Time frame: up to 24 hours]

Secondary outcome measures (1)

• Diaphragm thickness and excursion [Time frame: up to 24 hours]

Eligibility criteria

Inclusion criteria

Non-smokers Sedentary or recreationally active Normal lung function No history of claustrophobia

Exclusion criteria

Current smoking or vaping Obstructive lung disease Use of antibiotics or systemic corticosteroids to treat an acute condition History of sepsis or metastatic disease Post infectious conditions that affect breathing Diagnosed with a neurological or neuromuscular condition Any use of supplemental oxygen, continuous positive airway pressure (CPAP), or other positive pressure ventilation to treat sleep apnea Cardiac disease Orthopedic conditions that impair lung expansion Pregnancy Implanted metallic devices within 10 cm of the cervical spine

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Florida — Gainesville

Publications

• Ando R, Ohya T, Kusanagi K, Koizumi J, Ohnuma H, Katayama K, Suzuki Y. Effect of inspiratory resistive training on diaphragm shear modulus and accessory inspiratory muscle activation. Appl Physiol Nutr Metab. 2020 Aug;45(8):851-856. doi: 10.1139/apnm-2019-0906. Epub 2020 Feb 12. PMID 32049562
• Laghi F, Shaikh H, Littleton SW, Morales D, Jubran A, Tobin MJ. Inhibition of central activation of the diaphragm: a mechanism of weaning failure. J Appl Physiol (1985). 2020 Aug 1;129(2):366-376. doi: 10.1152/japplphysiol.00856.2019. Epub 2020 Jul 16. PMID 32673161
• Nierat MC, Similowski T, Lamy JC. Does trans-spinal direct current stimulation alter phrenic motoneurons and respiratory neuromechanical outputs in humans? A double-blind, sham-controlled, randomized, crossover study. J Neurosci. 2014 Oct 22;34(43):14420-9. doi: 10.1523/JNEUROSCI.1288-14.2014. PMID 25339753
• Locher C, Raux M, Fiamma MN, Morelot-Panzini C, Zelter M, Derenne JP, Similowski T, Straus C. Inspiratory resistances facilitate the diaphragm response to transcranial stimulation in humans. BMC Physiol. 2006 Jul 29;6:7. doi: 10.1186/1472-6793-6-7. PMID 16875504
• Hawkes EZ, Nowicky AV, McConnell AK. Diaphragm and intercostal surface EMG and muscle performance after acute inspiratory muscle loading. Respir Physiol Neurobiol. 2007 Mar 15;155(3):213-9. doi: 10.1016/j.resp.2006.06.002. Epub 2006 Jul 18. PMID 16846758
• Fauroux B, Isabey D, Desmarais G, Brochard L, Harf A, Lofaso F. Nonchemical influence of inspiratory pressure support on inspiratory activity in humans. J Appl Physiol (1985). 1998 Dec;85(6):2169-75. doi: 10.1152/jappl.1998.85.6.2169. PMID 9843540
• Bresciani G, Beaver T, Martin AD, van der Pijl R, Mankowski R, Leeuwenburgh C, Ottenheijm CAC, Martin T, Arnaoutakis G, Ahmed S, Mariani VM, Xue W, Smith BK, Ferreira LF. Intraoperative phrenic nerve stimulation to prevent diaphragm fiber weakness during thoracic surgery. PLoS One. 2025 Apr 1;20(4):e0320936. doi: 10.1371/journal.pone.0320936. eCollection 2025. PMID 40168300

Identifiers

NCT: NCT07427121 · IRB202501849

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗