Respiratory Muscle Training in Subacute Stroke Patients (RETORNUS)

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.

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.

Sham IMT at a fixed workload of 10 cmH2O. 5 sets of 10 repetitions, twice a day, 7 days per week, for 4 weeks.

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.

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

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

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

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.

Comorbidity variables (occurrence of complications, hospital admissions, hospital length of stay) and mortality.

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).

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