Respiratory Muscle Training in Subacute Stroke Patients (RETORNUS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02125760
Recruitment Status : Completed
First Posted : April 29, 2014
Last Update Posted : February 17, 2016
Information provided by (Responsible Party):
Esther Marco Navarro, Parc de Salut Mar

Brief Summary:
This study is divided for development in two complementary work packages justified by the need to incorporate new strategies to optimize rehabilitation outcomes in stroke patients. The general objectives are: 1) to determine the prevalence of respiratory muscle dysfunction in stroke patients; 2) to identify the existence of a potential amino acid marker of increased risk of muscle dysfunction after suffering a stroke; 3) to evaluate the effectiveness of incorporating the respiratory muscle training as an innovative adjuvant therapy in stroke rehabilitation program that may decrease the incidence of morbidity and mortality in the medium and long term; and 4) to quantify the potential impact of respiratory muscle training on the costs of care for stroke patients.

Condition or disease Intervention/treatment Phase
Muscle Weakness Other: Inspiratory Muscle Training (IMT) Other: High-intensity IMT Not Applicable

Detailed Description:

Stroke is a major cause of morbidity and mortality worldwide. It determines a substantial socioeconomic burden. Stroke can lead to varying degrees of oropharyngeal dysphagia (25-85% of patients) and respiratory muscle dysfunction associated with an increase in medical complications such as bronchoaspiration pneumonia, malnutrition and death. The respiratory muscle dysfunction is a common functional abnormality in chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), heart failure, multiple sclerosis in which it has been shown to modify the expected survival. Dysphagia is present in a significant proportion of patients admitted to Rehabilitation (up to 85% depending on series) in the subacute phase of stroke. There is no drug able to restore the swallowing function and inspiratory and expiratory muscle function in these patients. Consequently, neurological rehabilitation is the mainstay of treatment of these disorders.

Amino acids (AA) are essential for proper protein synthesis. Skeletal muscle represents the largest reserve of body AA, which may be used according to metabolic needs. Within this group of compounds, the most involved in muscle metabolism are glutamate, aspartate, asparagine, valine, leucine and isoleucine. A pathobiological association between decrease in muscle glutamate and diaphragm dysfunction in patients with chronic respiratory diseases has been demonstrated in chronic respiratory patients. Moreover, glutamate levels of the diaphragm can be restored as a result of muscle training, playing a decisive role as a precursor of certain AA (glutamine and alanine), and glutathione in patients with COPD. Other studies have defined that glutamine may be a biomarker of training response in healthy individuals. Several publications have reflected the decrease of glutamine and glutamate as a result of different diseases and in some cases have tried to supplement this deficit.

Muscle dysfunction is defined as a function impairment (decrease in strength and/or resistance) of muscles whose main consequence is muscle fatigue. Although exercise training has been used successfully to restore function in patients with some chronic illnesses and frailty, there is little evidence of the beneficial effects of an overall muscle training in stroke patients. Regarding peripheral muscles, a high-intensity training improves strength and endurance of lower limbs muscles (paretic and non paretic) in stroke patients. Dysfunction of the diaphragm and other respiratory muscles has important clinical implications. It associates with susceptibility to hypercapnic ventilatory failure, ineffective cough, and even higher incidence of repeated hospital admissions and mortality. Therefore, respiratory muscle weakness described in some stroke patients justifies the need to train respiratory muscles because there is no general exercise (bicycle, legs, arms) able to induce an overload enough to achieve training effect on respiratory muscles.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 129 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The RETORNUS Study: Dual Training to Restore the Function of Respiratory Muscles in Stroke Patients
Study Start Date : March 2011
Actual Primary Completion Date : December 2013
Actual Study Completion Date : September 2014

Arm Intervention/treatment
Sham Comparator: Inspiratory Muscle Training (IMT)
Patients with subacute stroke in a neurorehabilitation setting.
Other: Inspiratory Muscle Training (IMT)
Sham IMT at a fixed workload of 10 cmH2O. 5 sets of 10 repetitions, twice a day, 7 days per week, for 4 weeks.
Other Name: No applicable
Experimental: High-intensity IMT
Patients with subacute stroke in a neurorehabilitation setting.
Other: High-intensity IMT
High Intensity IMT. The training load is the maximum inspiratory load defined according to patient tolerance. This load will be equivalent to 10 maximal repetitions (RM) as 10 consecutive inspirations (x 5 sessions), twice a day.
Other Name: Short duration respiratory muscle training

Primary Outcome Measures :
  1. Respiratory muscle strength [ Time Frame: 3 weeks ]

    Respiratory muscle strength is assessed through maximal inspiratory and expiratory pressures (MIP and MEP, respectively) using a pressure transducer connected to a digital register system. The MIP is measured at mouth during a maximum effort from residual volume against occluded airway. To determine the MEP, the patients will perform a maximum expiratory effort from total lung capacity (TLC) in the face of the occluded airway. A specific and validated respiratory pressures manometer will be used (Micro RPM, Cardinalhealth, Kent, UK). For the purposes of the study, 'responders' will include the group of patients with an increase of 25% or more in respiratory muscle strength (MIP and MEP).

    Measures will be done once every week

Secondary Outcome Measures :
  1. Handgrip strength assessment [ Time Frame: 3 weeks ]

    Handgrip strength will be assessed during maximal voluntary isometric contraction of the flexor muscles of the fingers, using a dynamometer (JAMAR, Nottinghamshire, UK). We consider both the non-dominant and dominant hand. Reference values are those from Webb et al. (J Par Ent Nutr 1989, 13:30-3).

    Measures once every week

  2. Lower limb strength measurement [ Time Frame: 3 weeks ]

    Lower limb strength will be measured during a maximal voluntary isometric knee extension while the patient is sit in a bank of exercise (DOMYOS HG 050, Decathlon, France). An isometric dynamometer Nicholas Manual Muscle Tester (NMMT) (Lafayette Instrument Company, Lafayette, Indiana) will be used according to Dunn JC (J Phys Ther Ger 2003).

    Measures once every week

  3. Serum aminoacids analysis [ Time Frame: Up to 3 weeks ]
    Analysis of plasma samples (high performance liquid chromatography (HPLC) will determine levels of glutamine, valine, isoleucine, leucine and glutamate at baseline and at the end of muscle training using the technique previously described and validated (Clin Chem 1988, 34 (12): 2510-3). Venous blood samples will be collected in heparinized tube and centrifuged to obtain plasma. Later proceed to deproteinization with sulfosalicylic acid for analyzing the concentration of amino acids (AA). Finally the sample will be frozen at -80 º C for further analysis.

  4. Adverse events as a measure of safety and tolerability [ Time Frame: 18 months after discharge ]
    Comorbidity variables (occurrence of complications, hospital admissions, hospital length of stay) and mortality.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Hemiplegia secondary to first ischemic stroke in the subacute phase, and
  • informed consent signed by the candidates of the study, after receiving full information on objectives, techniques and possible consequences.

Exclusion Criteria:

  • Serious cardiovascular, neuromuscular or metabolic conditions that could interfere with the results and/or interfere with the measurements,
  • significant alcohol abuse (> 80 g/day) or severe malnutrition, and
  • treatment with drugs with potential effect on muscle structure and function (steroids, anabolic steroids, thyroid hormones and immunosuppressants).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02125760

Physical Medicine and Rehabilitation Dpt. Parc de Salut Mar, Hospital del Mar
Barcelona, Spain, 08003
Sponsors and Collaborators
Parc de Salut Mar
Study Director: Esther Duarte, MD, PhD Institut Hospital del Mar d'Investigacions Mèdiques. Universitat Autònoma de Barcelona.


Responsible Party: Esther Marco Navarro, MD, Parc de Salut Mar Identifier: NCT02125760     History of Changes
Other Study ID Numbers: PSM/RHB/NR/14
RETORNUS ( Other Identifier: PSMAR )
First Posted: April 29, 2014    Key Record Dates
Last Update Posted: February 17, 2016
Last Verified: February 2016

Keywords provided by Esther Marco Navarro, Parc de Salut Mar:
Respiratory muscle training

Additional relevant MeSH terms:
Muscle Weakness
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Signs and Symptoms