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Respiratory Muscle Training Reduces Respiratory Complications and Improves Swallowing Function After Stroke: A Systematic Review and Meta-Analysis

Open AccessPublished:November 12, 2021DOI:https://doi.org/10.1016/j.apmr.2021.10.020

      ABSTRACT

      Objective

      To investigate if respiratory muscle training is capable of reducing the occurrence of respiratory complications and improving dysphagia (swallowing or cough function) after stroke?

      Design

      Systematic review of randomized control trials based on the Cochrane guidelines.

      Participants

      Patients (> 18 years old) were diagnosed with stroke.

      Intervention

      Respiratory muscle training aimed at increasing respiratory muscles’ strength by using the threshold resistance trainer or flow-oriented resistance trainer.

      Outcome measures

      Respiratory complications, swallowing and cough function.

      Results

      Eleven trials (n=523 participants) were included . Respiratory muscle training reduced the risk of respiratory complications (RR0.51, 95%CI 0.28 to 0.93, I2 = 0%,P=0.03, ARD =0.068, NNT=14.71) compared with no/sham respiratory intervention. It also decreased the liquid type PAS scores by 0.81 (95% CI -1.19 to -0.43, I2 = 39%, P<0.0001). There was no significant association between respiratory muscle training and FOIS scores, cough function:increased FOIS scores by 0.47 (95%CI -0.45 to 1.39, I2 = 55%, P=0.32), decreased PECF-VC by 18.70 L/min (95%CI -59.74 to 22.33, I2 = 19%, P=0.37) and increased PECF-RC by 0.05 L/min (95% CI -40.78 to 40.87 I2 = 0%, P=1.00) .

      Conclusion

      This meta-analysis provided evidence that respiratory muscle training is effective in reducing the risk of respiratory complications, and improving dysphagia by reducing penetration or aspiration during swallowing liquid bolus after stroke. However, there was no sufficient evidence to determine that respiratory muscle training improves cough function. Additional multi-center studies using larger patient cohorts are required to validate and support these findings. Furthermore, long-term follow-up studies should be performed to measure outcomes, at the same time avoiding bias due to confounding factors such as heterogeneity of the etiologies of dysphagia.

      Key words

      Abbreviations

      PAS
      Penetration-Aspiration Scale
      FOIS
      Functional Oral Intake Scale
      PECF-VC
      Peak Expiratory Cough Flow of Voluntary Cough
      PECF-RC
      Peak Expiratory Cough Flow of Reflex Cough
      PEFR
      Peak Expiratory Flow Rate
      CVA
      Cough Volume Acceleration)
      MD
      Mean Difference
      SMD
      Standardised Mean Difference
      RR
      Relative Risk
      ARD
      Absolute risk difference
      NNT
      Number need to treat
      CI
      Confidence Interval
      MIP
      maximal inspiratory pressure
      MEP
      maximal expiratory pressure
      RCT
      Randomised Clinical Trial
      Dysphagia is a very common complication observed in stroke patients. The incidence rate is highly variable. It is lowest when identified using screening methods, i.e. the water swallow test, approximately 37%∼ 45%, while it is the highest when identified using instrumental testing, i.e. videofluoroscopy, with an incidence rate of 64%∼78%.1 Aspiration is associated with an 11-fold increase in the risk of chest infections or pneumonia1 which is one of the most troublesome respiratory complications after stroke, and may result in death2. Using pooled analysis from studies with sufficient data, the risk of pneumonia was found to be increased in patients with dysphagia, especially in patients with aspiration (RR=11.56, 95% CI 3.36-39.77).1 Furthermore, patients who develop pneumonia have higher mortality rates, longer hospitalization, poorer functional outcomes, and higher care needs.2,3 Although some studies have reported that approximately 90% of patients with dysphagia usually improve spontaneously with a return of safe swallowing function within two weeks,1,4 given the severity of post-stroke respiratory complications, appropriate and effective early interventions for dysphagia is crucial.
      Clinical therapy for dysphagia can be broadly divided into compensatory and remedial approaches. The compensatory approach aims to provide safer swallowing with control of food intake, material, viscosity, and the use of specific postures (e.g.chin tuck, head rotation, and tilting).5 However, the effect of this approach is partial and temporary. This is because the patients’ secretions (saliva) mixed with bacteria are much more likely to cause pneumonia or chest infections compared with food intake.6 The close association between the aspiration of bacteria-laden secretions and the development of pneumonia has been well documented.6,7 Langdon et. al.8 reported that of the 13 respiratory infections that were documented, six (46%) were observed in survivors who were ‘‘nil by mouth”. Hence their infections were unlikely a result of aspirating food or fluids compared to their saliva secretions.Compared to compensatory-based approaches, remedial-based approaches to swallowing therapy focus on rehabilitating damaged neural and musculoskeletal structures that contribute to dysphagia through various exercises and maneuvers (e.g. Mendelsohn maneuver, supraglottic swallowing, and neuromuscular electrical stimulation).9,10 in people with stroke.Dysphagia in people with a history of stroke is often characterized by impairments in both swallowing efficiency and safety, as well as impairments in spatial and temporal pharyngeal swallowing kinematics." 1Aspiration has been found to cause approximately 60 percent of post-stroke pneumonia.11 Hence, the pharyngeal phase is the most important, because aspiration is most likely to occur during this phase.12
      Breathing and swallowing processes occur through similar anatomical pharyngeal structures and are controlled by the brain stem in common. The two processess must be closely coordinated because they cannot be performed simultaneously.13 Also, the two coordinated processes provide important functions related to airway protection, such as forceful coughing. Good evidence shows that reduced levels of cough flow indicate the need for assisted airway clearance and is associated with higher risk of aspiration, and therefore aspiration pneumonia in stroke.14,15 However, weakness in the respiratory muscles and lack of the required coordination secondary to central nervous lesions can lead to swallowing impairment and ineffective cough after stroke. This predisposes patients to aspiration, secretion retention, pneumonia, or even respiratory failure .16,17 Thus respiratory (inspiratory and/or expiratory) muscle training may be a therapeutic strategy to reduce aspiration risk and prevent respiratory complications to improve swallowing function and effective cough in stroke survivors.
      To our knowledge, only one systematic review18 examined the effect of respiratory muscle training on reducing pneumonia incidence after stroke. The likelihood of respiratory complications was observed to have reduced significantly in patients after intervention (RR=0.38, 95% CI 0.15 to 0.96, I2 = 0%) compared to patients who received no/sham respiratory intervention. However, the study only included two trials19,20 (n = 179 participants) and failed to further explain the reason for lower pneumonia incidence after intervention. Three systematic reviews21-23 have examined the effect of expiratory muscle training on swallowing function. The review by Renata et. al.21 failed to find clear evidence due to heterogeneity in the etiologies and differences in the methods that summarized participant performance. The review by Marinda et. al.22 included three studies, using four different outcome measures (PAS, FOIS, sEMG of suprahyoid muscles activity, and hyolaryngeal movement). This study demonstrated that expiratory muscle training resulted in decreased aspiration, with a large effect for fluids and a moderate effect for solids. The meta-analysis performed by Zhuo et. al.,23 included five studies that reported PAS scores. They found that compared to the control group, patients in the expiratory muscle training group had a significant reduction in PAS scores (RR = −0.94, 95% CI = −1.27 to −0.61, P < 0.01). With regards to cough function after stroke, only a very few systematic reviews have examined the effect of respiratory muscle training. The meta-analysis performed by Zhuo et. al.,23 included four studies that analyzed cough function, with two outcomes, i.e., peak expiratory flow rate (PEFR) and cough volume acceleration (CVA). However, this meta-review failed to observe any impact on PEFR or CVA (RR = 0.57, 95% CI 0.62–1.77, P = 0.35; RR = 33.87, 95% CI −57.11 to 124.85, P = 0.47, respectively). The systematic review by Lucy et. al.,24 only included two trials that evaluated cough function in an adult population. No significant impact of expiratory muscle training on PECF-VC (increased by 4.63L/min; 95%CI -27.48 to 36.74; P=0.78) was observed. However, all the reviews mentioned above analyzed patients with dysphagia from a variety of neurological diseases or from healthy adults. Hence heterogeneity of the etiologies confounded their findings. Furthermore, in addition to voluntary cough function, reflex cough function should also be examined. Several studies have demonstrated that reflex cough is also associated with pneumonia risk14,15 and the function of reflex cough may be more important compared to voluntary cough in ensuring adequate airway protection and clearance after stroke.25,26 Hence, there is a need for a more updated review of the current evidence on the effectiveness of respiratory muscle training.
      The research questions for this systematic review were:
      • 1
        Does respiratory muscle training reduce the occurrence of respiratory complications in stroke survivors?
      • 2
        Does respiratory muscle training improve dysphagia (swallowing and cough function) after a stroke?

      METHOD

       Search strategy

      All searches were conducted before 2021-08-10, using the COCHRANE LIBRARY, EMBASE, PUBMED, and WEB of SCIENCE for studies published in English, and CBM, VIP, CNKI, and WANFANG databases for studies published in Chinese. MeSH terms combined with free terms were used to search for potentially relevant articles across databases and keywords were structured using the population, intervention approach, such as “Breathing Exercises”,“Respiratory Muscle Training”,“Maximal Respiratory Pressures” and “Stroke”. Full search strategies are presented in Appendix 1. This study conforms to all PRISMA guidelines and reports the required information accordingly.Using predetermined inclusion and exclusion criteria, two researchers who both are specialized in rehabilitation medicine independently screened each item for relevance by title and abstract. In cases where a decision could not be made as to whether the eligibility criteria were met based on the title and abstract, the full text of the article was obtained. More rigorous and comprehensive screening were used for 52 full texts, through retrieving the study designs, specific interventions, chacteristics of participants and outcomes. After evaluating full-text articles, 41 studies failing to meet the inclusion criteria were excluded. Finally, 11 studies were included in this systematic review. Fig. 1 outlines the flow of studies through the review. There was no potential for bias within the two researchers and disagreements or ambiguities were resolved by consensus with a third co-author.

       Eligibility criteria

      The studies were included if they met the PICOS criteria as follows:
      Participants (P):All of patients were adults (> 18 years old) diagnosed with stroke;
      Intervention(I):and Control (C): Respiratory muscle training aimed at increasing strength of the inspiratory and/or expiratory muscles by using threshold resistance trainer or flow-oriented resistance trainer was considered as the intervention; sham intervention without effective respiratory muscle training or no intervention was considered as the control;
      Outcomes(O):The occurrence of respiratory complications (lung infections and/or pneumonia) as primary outcome; swallowing function and cough function as secondary outcomes;
      Study design(S):Randomized controlled trials.
      Studies were excluded if (a) they were systematic reviews, tutorial articles, conference abstracts or single case reports; (b) they were failed to get full texts or extract valid outcome data; (c) they limited to describing immediate effects rather than outcomes after a course of treatment; (d)participants had swallowing dysfunction before stroke; (e) except stroke, participants also had the other diseases which might affect outcomes, such as heart disease,chronic obstructive pulmonary disease, spinal deformity etc.

       Quality Assessment

      The Cochrane risk-of-bias criteria 27 for assessing the risk of bias was used to evaluate the methodological quality of each included randomized controlled trial. There are seven items that assess bias, including random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. Each item was categorized as low risk, high risk, or unclear risk under the guidelines in the Cochrane Handbook. Other bias in this review was defined as trials in which baseline characteristics were not similar between different intervention groups. The GRADE evidence profile was provided to present information about the body of evidence, and judgments about the certainty of underlying evidence for each outcome.

       Data synthesis and analysis

      Two reviewers independently extracted data and information. Basic information, such as the first author's name, publication year, study design, patient characteristics, and intervention details, was extracted and analyzed. Primary outcome is the occurrence of respiratory complications which was extracted as number of participants with diagnosis of pneumonia or lung infection after training commencement. Secondary outcomes would be represented swallowing and cough function, such as the PAS scores, FOIS scores, PECF-VC and PECF-RC. The PAS is a standard tool used by both researchers and clinicians to assess penetration, aspiration, and swallowing safety 28 Laryngeal penetration is defined as passage of material into the larynx, which does not pass below the vocal folds, and aspiration refers to material penetrating the larynx and entering the airway below the true vocal folds. The scale is divided into 8 different levels based on the depth of material penetration into the airway and whether or not the material entering the airway is expelled. Higher levels indicate a greater degree of aspiration severity. Aspiration is judged to be more severe than penetration. Therefore, aspiration is scored 6, 7, or 8. Penetration, on the other hand, is scored either 2 or 3 if residue remains above the vocal folds and 4 or 5 if residue courses to the level of the vocal folds.29
      The FOIS was developed by Crary etc.30 in 2005 as a tool with very good reliability, validity, and sensitivity to objectively determine and monitor the range of oral intake of patients with neurogenic dysphagia. It is an ordinal scale with seven tiers that assesses the oral intake of food and liquids. Different ranges of non-oral feeding are subsumed in levels 1–3, whereas different ranges of oral feeding are included in levels 4–7. Level 1 indicates complete impairment of oral intake whilst a level 7 rating indicates that the patient has complete oral intake regardless of food consistency or type.
      The PECF was used as a surrogate marker for effective cough, which is an important defense against penetration and aspiration.31It was measured by having the patient inspire fully and then cough forcibly through a mask or mouthpiece attached to a peak flow meter. Voluntary cough was assessed by asking participants to make repeated maximal cough efforts into a tight-fitting face mask. Involuntary coughs were usually induced by the nebulization of escalating concentrations of capsaicin through the face mask.
      The PECF less than 160 L/min identifies patients with an ineffective cough. Patients with the PECF between 160 and 270 L/min are at risk of respiratory tract infections, which can further decrease muscle strength.31-34
      The meta-analysis was performed using Review Manager 5.3 software based on the preferred reporting items of the systematic review and meta-analysis guidelines. Heterogeneity was assessed by examining the clinical characteristics of the included studies and by formal statistical testing with χ2 and I2. For the assessment of swallowing function (PAS/ FOIS scores), inverse variance estimates with a fixed-effect analytical model preferred to be used to calculate the MD (Mean Difference) or SMD (Standardised Mean Difference) and their 95% CI. For the occurrence of respiratory complications,the Mantel-Haenszel method with a fixed-effect analytical model preferred used to calculate RR (Relative Risk) and ARD (Absolute risk difference), and 95% CI. If zero events were reported for one group in a comparison, a value of 0.5 was added to both groups for each such study. Based on the practice recommendation of the Cochrane Handbook27 trials with zero events in both the intervention and the control groups were not included in the meta-analysis when RR were calculated. If there were significant between-trial heterogeneity according to the judgment before the calculation,sensitivity analysis, subgroup analysis or meta-regression would be used to try to explain the source of heterogeneity and resolve it. On the contrary, if heterogeneity was failed to resolve, a randomized-effect analytical model was applied to calculate.

      RESULTS

       Flow of trials through the review

      The search strategy identified 2334 potentially relevant papers, but 589 were duplicates. After screening titles, abstracts and reference lists, 52 potentially relevant full articles were screened. After evaluating full-text articles, 41studies failing to meet the inclusion criteria were excluded, and 11 studies were included in this systematic review. Fig. outlines the flow of studies through the review.
      Fig 1. The flow of search strategy

       Characteristics of included trials

      The eleven trials19,20,35-43 involved 523 participants and investigated the effect of respiratory muscle training on respiratory complications (n =7), swallowing function (n=5) and cough function (n=4) after stroke. Ten studies did respiratory muscle training with threshold resistance trainer for inspiratory muscle and/or expiratory muscle, the trainer was set to various pressures, ranging from 30% to 60% MIP (Maximal Inspiratory Pressure) or 15% to 75% MEP (Maximal Expiratory Pressure).One study did respiratory muscle training with flow-oriented resistance trainer which the resistance was adjusted according to tolerance. Two of included trials19,37 carried out with three arms of interest: inspiratory muscle training, expiratory muscle training and sham training. For the outcome “ respiratory complications ” and “cough function ”, data of each experimental subgroup were combined in different approaches respectively to create a single comparison, following Cochrane recommendations.27 Additional relevant characteristics of the included studies and intervention are shown in Table 1.and Table 2.
      Table 1Characteristic of included trials.
      Study

      Design
      Intervention

      Outcome

      Measurement of Rc or Cf
      Frequency and durationParameters
      Eom MJ35

      2017

      Korea

      RCT’

      (NR)

      N=26

      Exp(n=13):EMT

      25reps × 5/wk × 4wk

      Con(n=13):sham (no loading)

      25reps × 5/wk × 4wk
      Muscles= expiratory

      Device= EMST150

      Resistance=70% MEP

      Progression= fixed
      Swallowing Function: PAS(0-8) (by VFSS)

      Timing:0, 4wk
      Guillen-Solà A36

      2016

      Spain

      RCT

      (computer-

      generated random list)

      N=33
      Exp1(n=16):IEMT

      50reps × 2/d × 5/wk × 3wk

      Con(n=17):nothing

      Muscles= inspiratory+ expiratory

      Device= Orygen-Dual Valve

      Resistance= 30% MIP+30% MEP

      Progression= resistance increased weekly at intervals of 10 cmH2O
      Respiratory complications:

      pneumonia

      Swallowing Function:

      PAS(0-8) (by VFSS)

      FOIS(1-7)

      Timing:0, 3,12wk
      Rc: Chest x-ray or by fever with abnormal respiratory signs(medical reports and/or telephone interview).

      Timing: 0, 12wk.
      JinJuan W 37

      2019

      China
      RCT’

      (NR)

      N=98
      Exp1(n=33):EMT

      50reps x 4/wk x 90d

      Exp2(n=32):IMT

      50reps x 4/wk x 90d

      Con(n=33):sham(10% MIP/MEP)

      50reps x 4/wk x 90d

      Muscles= inspiratory or expiratory

      Device=NR

      Resistance=50% MIP or 50%MEP

      Progression =resistance readjusted according to tolerance

      Respiratory complications: pneumonia

      Cough Function:

      PECF-VC (L/min)

      PECF- RC (L/min)

      Timing:0, 28, 90d
      Rc: Chest x-ray or by fever with abnormal respiratory signs(medical reports and/or telephone interview).

      Timing:0, 90d.

      Cf: Comprehensive lung function instrument (VIA- SYS,USA)

      VC: Repeated maximal cough efforts

      RC: Induced by the capsaicin

      Timing:0, 28, 90d
      Kulnik ST19

      2015

      United Kingdom
      RCT

      (random number)

      N=78
      Exp1(n=27):EMT

      50 reps x 7/wk x 4 wk

      Exp 2(n=26):IMT

      50 reps x 7/wk x 4 wk

      Con(n=25):sham (10% of maximal mouth pressure)

      50 reps x 7/wk x 4 wk

      Muscles= inspiratory or expiratory

      Device= NR

      Resistance=50%MIP or 50%MEP

      Progression= resistance adjusted to 50% of maximal strength weekly

      Respiratory complications: pneumonia

      Cough Function:

      PECF-VC (L/min)

      PECF-RC (L/min)

      Timing:0, 28, 90d
      Rc: Temperature >37.5°C on 2 consecutive measurements or a single measurement of >38.0°C with chest symptoms, and ≥1 of the following: white cell count >11000/mL, pulmonary infiltrate on chest radiograph, positive microbiology cultures.

      Timing: 0, 90d.

      Cf: Calibrated pneumotachograph (PK Morgan Ltd, Rainham, England)

      VC: Repeated maximal cough efforts

      RC: Induced by the capsaicin

      Timing:0, 28, 90d
      Liaw MY38

      2020

      China (Taiwan)

      RCT

      (random number)

      N=21
      Exp(n=10):IEMT

      30reps × 1-2/d × 5/wk × 6wk

      Con(n=11):nothing



      Muscles= inspiratory + expiratory

      Device= Dofin Breathing Trainer

      Resistance= (30% - 60%) MIP + (15% -75%) MEP

      Progression= resistance was adjusted according to tolerance
      Swallowing Function:

      FOIS (1-7)

      Cough Function:

      PECF(L/min)

      Timing: 0, 6wk
      Cf: By a spirometer (Vitalograph, Serial Spirotrac, Buckingham, VA) as per the American Thoracic Society standards

      Timing: 0, 6wk
      Menezes KKP39

      2018

      Brazil

      RCT

      (random number)

      N=37
      Exp(n=19):IEMT

      40mins x 7/wk x 8wk

      Con(n=18):sham(0 cmH20)

      40mins x 7/wk x 8wk

      Muscles= inspiratory+ expiratory

      Device= Orygen-Dual Valve

      Resistance= 50%MIP+ 50% MEP

      Progression= resistance adjusted to 50% maximal strength weekly
      Respiratory complications

      Timing: 0,8,12wk
      Rc: By asking the participants whether and how often they were admitted to a hospital due to respiratory reasons.

      Timing:0,12wk.
      Messaggi-SartorM20

      2015

      Spain

      RCT

      (random number)

      N=101
      Exp(n=54):IEMT

      50reps × 2/d × 5/wk × 3wk

      Con(n=47):sham(10 cmH2O)

      50reps × 2/day × 5/wk × 3wk
      Muscles = inspiratory+ expiratory

      Device = Orygen-Dual Valve

      Resistance= 30% MIP+ 30%MEP

      Progression= resistance increased 10 cmH2O weekly
      Respiratory complications:

      lung infections

      Timing: 0, 3wk, 6mth
      Rc: Chest x-ray or fever with abnormal clinical respiratory signs(medical records and telephone interviews).

      Timing: 0, 6mth.
      Moon JH 40

      2017

      Korea

      RCT’

      (NR)

      N=18
      Exp(n=9):EMT

      30mins × 5/wk × 4wk

      Con(n=9):nothing

      Muscles= expiratory

      Device= EMST150

      Resistance=70% MEP

      Progression= fixed
      Swallowing Function:

      PAS (0-8) (by VFSS)

      Timing: 0, 4wk

      Park JS41

      2016

      Korea

      RCT

      (random envelopes)

      N=27
      Exp(n=14):EMT

      25reps × 5/wk × 4wk

      Con(n=13):sham (no spring loading)

      Muscles= expiratory

      Device= NR

      Resistance=70% MEP

      Progression= fixed
      Swallowing Function:

      PAS (0-8)

      FOIS (1-7)

      Timing: 0, 4wk
      Yoo HJ42

      2018

      Korea

      RCT

      (computer-

      generated random list)

      N=40
      Exp(n=20):IMT+EMT

      30mins × 2/day × 5/wk × 3wk

      Con(n=20):nothing

      Muscles= inspiratory+ expiratory

      Device= A flow-oriented incentive spirometer +The Acapella vibratory PEP device

      Resistance= Not quantitative

      Progression= resistance was adjusted according to tolerance
      Respiratory complications:

      pneumonia

      Timing: 0, 3wk
      Rc: Clinical findings: new lung infiltration on imaging studies plus clinical evidence that the infiltrate was of infectious origin, which includes the new onset of fever, purulent sputum, leukocytosis, and a decline in oxygenation.

      Timing: 0, 3wk.
      Choi-HE43

      2021

      South Korea
      RCT’

      (NR)

      N=44
      Exp(n=22):IMT+EMT

      30mins × 5/wk × 4wk

      Con(n=22):nothing

      Muscles= inspiratory+ expiratory

      Device= POWERbreathe (POWERbreathe International Ltd) + Threshold IMT/PEP (Philips Respironics)

      Resistance = 5-10cm H2O (POWERbreathe) + 50% MIP(Threshold IMT)+ 50%MEP(Threshold PEP)

      Progression =The pressure was increased by 2cm H2O(IMT) and 1 cm H2O(EMT) as the subjects became accustomed to the resistance
      Respiratory complications: pneumonia

      Cough Function:

      PECF-VC (L/min)

      Timing:0, 4wk
      Rc: Patient interviews and review of medical records for 1 yr after acute stroke.

      Timing: 0, 1yr.

      Cf: Asthma Mentor Peak flow meter (Respironics).

      Timing: 0, 3wk.
      Table 2Characteristic of interventions.
      Study

      Design


      Participants
      Stroke site /HemiplegiaExp(Exp1/Exp2)

      /Con n (%)
      Stroke aetiology / typeExp(Exp1/Exp2) / Con n (%)
      Eom MJ35

      2017

      Korea

      RCT’

      (NR)

      N=26

      Exp(n=13):

      Age(yr) =69.2±4.1

      Con(n=13):

      Age(yr) =70.2 ± 3.6

      Time since stroke(mth) <3

      All participants with dysphagia
      Middle cerebral artery

      Basal ganglia

      Midbrain

      Frontal lobe

      Internal capsule

      Pons

      9 / 9

      0 / 1

      1 / 0

      1 / 1

      1 / 1

      1 / 1
      Guillen-Solà A36

      2016

      Spain

      RCT

      (computer-

      generated random list)

      N=33
      Exp1(n=16):

      Age(yr) =67.9 ± 10.6

      Con(n=17):

      Age(yr) =68.9 ± 7.0

      1 ≤ Time since stroke(wk) ≤ 3

      All participants with dysphagia
      Right

      Left

      Bilateral/ataxia

      40% / 38.1%

      55% / 57.1%

      5% / 4.8%

      Atherosclerosis

      Cardioembolism

      Lacunar

      Other determined aetiology

      Undetermined aetiology

      Missing data
      30% / 28.6%

      35% / 33.3%

      0% / 9.5%

      0% / 0%

      35% / 23.8%

      0% / 4.8%
      JinJuan W 37

      2019

      China
      RCT’

      (NR)

      N=98
      Exp1(n=33):

      Age(yr) =66.43 ± 13.95

      Exp2(n=32)

      Age(yr) =62.67 ± 14.39

      Con(n=33):

      Age(yr) =64.07 ± 10.82

      Time since stroke(wk) ≤ 2

      Dysphagia=NR
      Left

      Right

      14 / 17 / 13

      19 / 15 / 20

      Ischemic

      Hemorrhagic

      26 / 23 / 29

      7 / 9 / 4

      Kulnik ST19

      2015

      United Kingdom
      RCT

      (random number)

      N=78
      Exp1(n=27):

      Age(yr) =65.7 ± 15.4

      Unsafe swallow =13 (48%)

      Exp2(n=26):

      Age(yr) =62.5 ± 14.6

      Unsafe swallow =10 (38%)

      Con(n=25):

      Age(yr) =65.1 ± 13.9

      Unsafe swallow =12(48%)

      Time since stroke(mth)≤ 0.5
      Left

      Right

      Bilateral

      Cortical

      Subcortical

      Brain stem/cerebellar

      10 / 8 / 11

      17 / 17 / 14

      … / 1 / …

      12 / 10 / 11

      14 / 12 / 8

      1 / 4 / 6

      Ischemic

      Hemorrhagic

      22 / 23 / 24

      5 / 3 / 1

      Liaw MY38

      2020

      China (Taiwan)

      RCT

      (random number)

      N=21
      Exp(n=10):

      Age(yr) =66.80 ±11.47

      Swallowing disturbance=6 (60.00%)

      Con(n=11):

      Age(yr) =61.18 ± 10.69

      Swallowing disturbance=8 (66.67%)

      Time since stroke(mth)=2.67±1.46
      Right

      Left

      40.00% / 33.33%

      60.00% / 66.66%

      Hemorrhage

      Ischemic

      40.00% / 66.66%

      60.00% / 33.33%

      Menezes KKP39

      2018

      Brazil

      RCT

      (random number)

      N=37
      Exp(n=19):

      Age(yr)=60 ± 14

      Con(n=18):

      Age(yr)=67 ± 11

      3mth≤Time since stroke ≤ 5yr

      Swallowing disorder:NR
      Right

      Left

      Unknown

      63% / 32%

      32% / 58%

      5% / 10%

      Ischemic

      Hemorrhagic

      Unknown
      63% / 79%

      16% / 16%

      21% / 5%

      Messaggi-SartorM20

      2015

      Spain

      RCT

      (random number)

      N=101
      Exp(n=54):

      Age(yr) =65.6 ± 11.4

      Dysphagia =81.7%

      Con(n=47):

      Age(yr) =67.6 ± 10.9

      Dysphagia =88.7%

      Time since stroke(wk)<3
      Right

      Left

      54% / 59%

      46% / 41%

      Cardioembolic

      Small vessel

      Undetermined

      Atherothrombotic
      20.4% / 24.5%

      18.5% / 18.9%

      33.5% / 30.2%

      25% / 18.9%
      Moon JH 40

      2017

      Korea

      RCT’

      (NR)

      N=18
      Exp(n=9):

      Age(yr) =63.0 ± 5.8

      Con(n=9):

      Age(yr) =63.1 ± 5.2

      Time since stroke(mth) ≤ 1

      All participants with dysphagia
      Left

      Right

      4 / 5

      5 / 4
      Ischemic

      Hemorrhagic

      6 / 7

      3 / 2

      Park JS41

      2016

      Korea

      RCT

      (random envelopes)

      N=27
      Exp(n=14):

      Age(yr) =64.3 ± 10.7

      Con(n=13):

      Age(yr) =65.8 ± 11.3

      Time since stroke(mth) ≤ 6

      All participants with dysphagia
      Middle cerebral artery

      Basal ganglia

      Midbrain

      Frontal lobe

      Internal capsule

      Corona radiate

      Pons

      5 / 4

      2 / 1

      2 / 1

      2 / 2

      1 / 2

      1 / 1

      1 / 2




      Yoo HJ 42

      2018

      Korea

      RCT

      (computer-

      generated random list)

      N=40
      Exp(n=20):

      Age(yr) =57 (34-82)

      Aspiration =10%

      Con(n=20):

      Age(yr) =65 (34-86)

      Aspiration =10%

      Time since stroke(mth) ≤ 3
      Right

      Left

      11 / 9

      9 / 11
      Ischemic

      Hemorrhagic

      11 / 12

      9 / 8

      Choi-HE43

      2021

      South Korea
      RCT’

      (NR)

      N=44
      Exp(n=22):

      Age(yr) = 67.6 ± 12.4

      Con(n=22):

      Age(yr) =67.2 ± 13.3

      Time since stroke(wk) ≤2 wk

      Dysphagia=NR
      Right

      Left

      Both

      None
      5 / 7

      15 / 11

      2 / 3

      0 / 1

      Ischemic

      Hemorrhagic

      16 / 15

      6 / 7

      Outcome measures listed are only those that were analysed in this systematic review.
      Exp= experimental group, Con= control group, EMT= expiratory muscle training, IMT= inspiratory muscle training, IEMT= inspiratory and expiratory muscle training, MEP= maximal expiratory pressure, MIP= maximal inspiratory pressure, PAS= Penetration-Aspiration Scale, FOIS= Functional Oral Intake Scale, PECF-VC= Peak Expiratory Cough Flow of Voluntary Cough, PECF-RC= Peak Expiratory Cough Flow of Reflex Cough, RCT= randomised clinical trial, reps= repetitions, NR= not reported, VFSS= Videofluoroscopic Swallowing Study, Rc= Respiratory complications, Cf= Cough function.

       Risk of bias assessment

      The outcomes of quality assessment of the studies were input into Review Manager Software (Version 5.3; Cochrane Collaboration) according to the quality assessment judgment criteria (Fig. 2, Fig. 3). The risks of bias were assessed as low, high, and unclear risk. Most of the studies had a low risk of bias for random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome data. All studies had a low risk of bias for incomplete outcome data, selective reporting, and other sources of bias. Seven trials were randomized clinical trials with clear method of randomization,19,20,36,38,39,41 and four trials alleged “RCT” (Randomised Clinical Trial) but with unknown methodology were defined as possible RCT. 35,37,40,43
      Fig. 2 Risk of bias summary
      Fig. 3 Risk of bias graph

       Participants

      The mean age of participants ranged from 34 to 86 years across trials. The mean time after stroke ranged from 8.8 days to 24months. And the majority of trials (87%) comprised participants who within 3 months of stroke onset on admission to the trial. In total of 242 stroke participants had dysphagia confirmed by VFSS or *BSA19 (*BSA by trained nursing staff, according to algorithm and including evaluation of level of consciousness, oromotor function, and trials of water/food; concerns trigger review by speech and language therapist).

       Intervention

      In all trials, the experimental intervention was respiratory muscle training which was delivered by threshold resistance trainer or flow-oriented resistance trainer. The respiratory muscle training targeted the expiratory muscles,20,35,40,41 a combination of inspiratory and expiratory muscles,36,38,39,42,43 inspiratory and expiratory muscles to separate participants.19,37 Participants undertook training for 30-40 minutes (or 25 to 50 repetitions), four to fourteen times per week, for 3 to 13 weeks. In all trials, the control intervention was nothing36,38,40,42,43or sham respiratory intervention .19,20,35,37,39,41Sham intervention was delivered via a threshold trainer with no resistance valve or a small resistance of the respiratory muscle strength(10% MIP/MEP or 10cmH2O).

       Outcome measures

      Occurrence of respiratory complications was measured in seven trials19,20,36,37,39,42,43 and reported as number of participants with pneumonia in five trial,19,36,37,42,43and as number of participants with lung infections in one trial20 after the commencement of the training. In Menezes’ trial,39 there is no specific information about respiratory complications. Swallowing function was measured in five trials,35,36,38,40,41using the PAS(1 to 8 points) in four trials35,36,40,41and FOIS(1 to 7 points) in three trials. 36,38,41Cough function was measured in four trials,19,37,38,43 using PECF-VC and /or PECF-RC.

       Respiratory complications

      The effect of respiratory muscle training on respiratory complications was examined by pooling the data from seven trials19,20,36,37,39,42,43 With the consideration of the impact of clinical heterogeneity, the Menezes KKP's study39was seperated because the time limitation “3mth≤Time since stroke ≤ 5yr ” which was totally at the chronic stage. And the others were at the early stage (acute and subacute stage, ≤ 3mth) . Therefore a total of six trials(n=394) in meta-analysis. The likelihood of respiratory complications was significantly lower after respiratory muscle training, (RR0.51, 95%CI 0.28 to 0.93, I2 = 0%, P=0.03) compared with no/sham respiratory intervention (Fig. 4).
      Figure 4
      Figure 4Respiratory complications Forest plot.tif
      ARD (Absolute risk difference) =0.068; NNT (Number need to treat) = 14.71
      Fig. 4 Relative risk (95% CI) of respiratory complications after respiratory muscle training versus no/sham respiratory intervention(n=394).

       Swallowing function

       PAS

      The effect of respiratory muscle training on swallowing function based on PAS was examined by pooling data from four trials,35,36,40,41however it failed to extracted data completely in the Guillen-Solà’s trial.36 Therefore a total of three trials(n= 71) in meta-analysis, when a fixed effects model was applied, respiratory muscle training decreased PAS scores by 0.81 (95% CI -1.19 to -0.43, I2 = 39%, P<0.0001), compared with no/sham respiratory intervention (Fig. 5).
      Fig. 5 Mean difference (95% CI) of effect of respiratory muscle training versus no/ sham respiratory intervention on PAS, in score (n =71).

       FOIS

      The effect of respiratory muscle training on swallowing function based on FOIS was examined by pooling data from three trials,36,38,41in Guillen-Solà’ s trial,36there is no specific post intervention data and it only reported that “ FOIS improved 0.76 (SD 1.1) points after completing intervention, and 1.76 (SD 1.1) points at 3-month follow-up”.Therefore a total of two trials(n= 48) in meta-analysis, when a random effects model was applied, there was no significant association between respiratory muscle training and the FOIS scores, increased by 0.47 (95% CI -0.45 to 1.39, I2 = 55%,P=0.32) compared with no/sham respiratory intervention (Fig. 6).
      Fig. 6 Mean difference (95% CI) of effect of respiratory muscle training versus no/sham respiratory intervention on FOIS, in score (n =48).

       Cough function

       PECF-VC

      The effect of respiratory muscle training on cough function based on PECF-VC was examined by pooling data from four trials19,37,38,43 (n=226), when a fixed effects model was applied, there was no significant association between respiratory muscle training and PECF-VC, decreased by 18.70 L/min (95%CI -59.74 to 22.33, I2 = 19%, P=0.37) compared with no/sham respiratory intervention (Fig. 7).
      Fig. 7 Mean difference (95% CI) of effect of respiratory muscle training versus no/ sham respiratory intervention on PECF-VC, in L/min (n =226).

       PECF-RC

      The effect of respiratory muscle training on cough function based on PECF-RC was examined by pooling data from two trials19,37 (n = 161), when a fixed effects model was applied, there was no significant association between respiratory muscle training and PECF-RC, increased by 0.05 L/min (95% CI -40.78 to 40.87 I2 = 0%, P=1.00) compared with no/sham respiratory intervention (Fig. 8).
      Fig. 8 Mean difference (95% CI) of effect of respiratory muscle training versus no/ sham respiratory intervention on PECF-RC, in L/min (n =161).

      DISCUSSION

      Safe swallowing can prevent foreign materials from aspirating into the airway during the swallowing process. An effective and strong voluntary cough could reduce penetration and aspiration by removing foreign materials, even after food enters the airway. Clinical interventions, such as improving swallowing or cough function, could reduce the occurrence of respiratory complications. Based on this assumption, this review set out to answer two questions: 1) Does respiratory muscle training reduce the occurrence of respiratory complications after stroke? 2) Does respiratory muscle training improve the swallowing function after stroke?
      For the first question, this meta-analysis demonstrated that respiratory muscle training reduced the relative risk of respiratory complications immediately or 3-12 months after treatment initiation for the stroke participants who were at the early stage. However, it failed to do the meta-analysis for stroke participants who were at the chronic stage because only one study reported by Menezes KKP39 was included. And it reported that there was no significant between-group difference for respiratory complications. Even the power of analysis was increased by applying strict inclusion criteria, several limitations must be addressed. First, in the majority of trials, the incidence between the end of the intervention period and the final follow-up were captured, with some lost on follow-up, and only one trial19 reported data on the intention to treat. Second, there are several independent risk factors for post-stroke pneumonia,44,45hence a statistical model that adjusted for potential con-founders for respiratory complications was required to apply in analysis for making sure the results precisely. Third, even though “the early and the chronic stage” were seperated to analysis, it failed to seperate “the early stage such as acute and subacute stroke stage” among the six studies further. It is assumed that a higher occurrence of respiratory complications manifests during the acute stage.1 Therefore, additional multi-center studies using larger patient cohorts and better methodological quality are required .
      For the second question, sufficient data was not provided to determine whether respiratory muscle training was able to improve swallowing function based on FOIS scores. Based on the liquid type PAS scores, preliminary evidence from three trials35,40,41demonstrated a reduction in the scores after respiratory muscle training. Possible explanations for this “seemingly contradictory result”could be due to several reasons: First, FOIS documents the functional level of oral intake food and liquid, also considering the use of enteral nutrition. Enteral nutrition may be necessary to avoid malnutrition in cases of severe dysphagia 46. PAS as an objective evaluation describes fundamental aspects of dysphagia, but, clinical outcome can be influenced by other important parameters, for example, awareness, collaboration, cognitive abilities, presence of apraxia, or speech impairment like aphasia, which can compromise the ability to understand language. The presence of these types of impairment can add further difficulties in the deglutition process and may reduce the success rate of swallowing treatment. Second, a previous cross-sectional study47 had demonstrated that FOIS, compared with PAS for identifying dysphagia for liquids, had a sensitivity of 6.3% and a specificity of 94.9%. For semisolids, the sensitivity was 6.1% and specificity was 95.5%. Thus, although the sensitivity of PAS is high, the specificity is lower than FOIS. Third, small sample size: a total of three trials(n= 71) were included and the result only reported the liquid type PAS scores. Because most of the trials only assessed the effects of the training using standard thin liquid bolus. Only the trail performed by Park et. al 41 evaluated training using semisolid bolus. After training, they found a significant difference in liquid type PAS scores, but not for the semisolid type PAS scores (P = 0.03 and 0.32 respectively). Comparing the levels of change for both groups, significant differences were observed for only liquid type PAS scores (P = 0.03) and not for semisolid type PAS scores (P = 0.38). Studies have shown that 62% of survivors were provided some form of modified diet or thickened fluids or were “nil by mouth” two days after hospital admission, which is comparable to the literature for subjects with first-ever stroke.48,49Hence it is important that future studies assess the swallowing function of oral intake of different bolus types to identify patterns of abnormal swallowing that may reflect different underlying etiologies of dysphagia.
      However, the positive result of the liquid type PAS scores suggested that respiratory muscle training reduced laryngeal penetration and aspiration during liquid bolus swallowing. This has potentially important implications for the management of dysphagia in stroke survivors. Similar results were observed in previous reviews22,23and showed that respiratory muscle training improved muscle and neural adaptations to recover swallowing function. Expiratory muscle training promotes the activation of the suprahyoid muscles that play a major role to elevate the hyolaryngeal complex and open the upper esophageal sphincter necessary for swallowing.50This is known to have a direct effect on decreasing aspiration and pharyngeal residues.51Furthermore, respiratory muscle training enhances the orofacial muscles, such as the submental, palatal, lingual, velopharyngeal, and pharyngeal musculature. This is important to coordinate bolus transport during swallowing, maintenance of swallowing safety and efficiency, and functional improvements.50 Lastly, afferent stimulation of the sensory receptors of the tongue and oropharynx provided by respiratory muscle training may increase the activity of the swallowing center in the medulla oblongata of the brainstem. 52,53
      Based on a previous study,54 voluntary coughs have been closely related to aspiration in terms of airway protection mechanism during swallowing. It was found that the intensity of coughing correlated with the risk of airway aspiration. The positive outcomes of respiratory muscle training on reducing PAS scores may indicate the ability to improve cough function. However, this meta-analysis failed to provide sufficient evidence to demonstrate any effects on PECF-VC or PECF-RC after respiratory muscle training. Possible explanations could be due to several reasons: First, even though the inspiratory and expiratory muscle strength after acute stroke patients were approximately half compared to healthy age-matched controls,55 the weakness in cough observed in stroke patients were shown to be related to reduced cortical influences that modulate cough production, rather than peripheral muscle weakness.55-57In addition to respiratory muscle weakness, changes in chest wall kinematics could also be responsible for impaired cough after stroke.57 Second, although an effective cough requires coordinated activation of inspiratory and expiratory muscles, PECF requires a short duration and isometric contraction of expiratory muscles to generate maximal pressure. This suggests that expiratory muscle strength is dominant in generating PECF. However, a previous meta-analysis58 demonstrated that respiratory muscle training improves inspiratory but not expiratory muscle strength. This is because active inspiratory volume is a precondition for forceful expiration or cough flow. Hence, it seems reasonable that longer training is required for restoring expiratory muscle strength. Additionally, reflex cough is believed to originate primarily in the brainstem in response to food swallowing or inhalation of noxious substance. Several studies have demonstrated that reflex cough is more important than a voluntary cough in ensuring adequate airway protection and clearance after acute stroke.59,26 However, reflex cough produced in the laboratory does not accurately replicate the response to aspirated fluids or food, which cannot be easily studied for safety reasons and patient discomfort considerations.60 In addition, it is worth noting that peak expiratory cough flow is only one aspect to reflect cough function. Because the limitation of small sample size, other equally important measures were not included in this review, such as cough expired volume or cough volume acceleration. Thus, more studies evaluating the cough function comprehensively are recommended, before drawing definitive conclusions regarding clinically worthwhile effects in the future.
      Lastly, in this meta-analysis review, one adverse event was reported in the trial conducted by Menezes et. al.39 The study participant who was in the experimental group terminated training after 2 weeks due to chest pain. The theoretical risks of elevated thoracic pressure or repeated Valsalva maneuvers performed in patients with stroke and/or cardiovascular comorbidities should be seriously considered during therapy.

       Limitation

      The main limitations of this review could be obviously known from the GRADE evidence profile. The small sample size was one of the most important factors leading to imprecision in this mete-analysis, especially for the outcome of PAS scores and FOIS scores, they only included 71 and 48 samples respectively. In addition, in total of 11 studies were included in this systematic review, six of them only recruited “ unilateral stroke”; five of them recruited both “ unilateral stroke” and “Bilateral stroke ”. There is no doubt that it is better to do subgroups analysis to make conclusions more precise. However, the subgroup analysis was blocked as we failed to get the original data. Also, even though the power of analysis was increased by applying strict inclusion criteria, the presence of various of risk of bias for each included study such as the risk of performance bias, attrition bias or detection bias became the other primary factors that lower the level of evidence. In view of the relative contradiction between enlarging the sample size and more rigorous studies’ screening process, the more high-quality randomized controlled trials are actively encouraged in the future to provide the high level of grade evidence.

       Conclusions

      This systematic review provides evidence that respiratory muscle training is effective in reducing the risk of respiratory complications (pneumonia/lung infection). Furthermore, it improved dysphagia by reducing penetration or aspiration during swallowing liquid bolus after stroke. The results of the meta-analysis indicated that 20-30 minutes of respiratory muscle training, five times per week, for 4-5 weeks could improve swallowing function and reduce the risk of respiratory complications after a stroke. However, no significant effects of respiratory muscle training on improving cough function after stroke were observed. Additional multi-center studies using larger patient cohorts are required to validate and support these findings. Furthermore, long-term follow-up studies should be performed to measure outcomes, at the same time avoiding bias due to confounding factors such as heterogeneity of the etiologies of dysphagia.

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      Appendix. Supplementary materials