The Effect of Inspiratory Muscle Training on Fatigue and Dyspnea in Heart Failure Patients

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O R I G I N A L A R T I C L E

The effect of inspiratory muscle training on fatigue and dyspnea in patients with heart failure: A randomized, controlled trial

Amir Hossein Hossein Pour¹ | Mohammad Gholami² | Mandana Saki³ | Mehdi Birjandi⁴

1Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran

2School of Nursing and Midwifery, Lorestan University of Medical Sciences,

Khorramabad, Iran

3Social Determinants of Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran

4Department of Biostatistics and Epidemiology, School of Health and Nutrition, Lorestan University of Medical Sciences, Khorramabad, Iran

Correspondence

Mohammad Gholami, School of Nursing and Midwifery, Lorestan University of Medical Sciences

Khorramabad, Iran.

Email: [email protected]

Funding information

Funding for this study was provided by the Research and Technology Deputy of Lorestan University of Medical Sciences with the project code: A-10-1,661-1.

Abstract

Aim:Fatigue and dyspnea are debilitating symptoms in patients with heart failure (HF). The purpose of this study was to evaluate the effects of inspiratory muscle training (IMT) on dyspnea, fatigue and the New York Heart Association (NYHA) functional classification in patients with HF.

Methods: In this prospective, randomized, controlled trial, 84 patients with HF (NYHA classes II-III/IV) with a mean age of 56.62 ± 9.56 years were randomly assigned to a 6-week IMT (n= 42) or a sham IMT (n= 42) program. The IMT was performed at 40% of the maximal inspiratory pressure (MIP) in the IMT group and at 10% in the sham group. The main outcomes were assessed at baseline and after the intervention and included dyspnea severity scale (Modified Medical Research Council [MMRC], Fatigue Severity Scale [FSS] and the NYHA functional classification (based on the presenting symptoms).

Results: The between-group analysis showed significant improvements in dyspnea, fatigue and the NYHA functional classification in the IMT group compared to the sham group (P < .05). The within-group analysis showed significant improvements in dyspnea (from 2.63 ± 0.79 to 1.38 ± 0.66, P < .001), fatigue (from 43.36 ± 8.5 to 28.95 ± 9.11,P< .001) and the NYHA functional classification (from 2.73 ± 0.5 to 2.1 ± 0.6,P= .001) in the IMT group, while fatigue and dyspnea increased significantly in the sham group.

Conclusions:The 6-week home-based IMT was found to be an effective and safe tool for reducing dyspnea and fatigue and improving the NYHA functional classification.

K E Y W O R D S

dyspnea, fatigue, heart failure, inspiratory muscle training

1 | I N T R O D U C T I O N

Heart failure (HF) is an incapacitating chronic condition (Conley, Feder, & Redeker, 2015). Although there have been significant advances in optimizing drug management for patients with HF, the personal and social burden of this disease is still characterized by debilitating symptoms and re-hospitalization (Smart, Giallauria, & Dieberg, 2013).

Patients with HF often experience generalized muscle atrophy, including inspiratory muscle atrophy. Weakness of the respiratory muscles during exercise and activity can cause fatigue and dyspnea (Montemezzo, Fregonezi, Pereira, Britto, & Reid, 2014).

Dyspnea is a hallmark symptom of HF (Kupper, Bonhof, Westerhuis, Widdershoven, & Denollet, 2016). In a study conducted on patients with HF, the incidence of severe

DOI: 10.1111/jjns.12290

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dyspnea was reported as 69% (Perez-Moreno et al., 2014).

The mechanism of dyspnea is multifactorial. One study found that the somatic symptoms of depression and anxiety are the strongest determinants of dyspnea. Dyspnea is also significantly associated with factors such as older age, chronic obstructive pulmonary disease (COPD), body mass index (BMI) and inflammatory factors such as interleukin-6 and 10 (Kupper et al., 2016). Dyspnea can exacerbate fatigue in patients with HF by restricting their daily activities (Tsai et al., 2013).

Fatigue is also a prototypical symptom of HF. In one study, 59% of the patients with HF reported moderate to severe fatigue (Perez-Moreno et al., 2014). Fatigue is a reflection of muscle hypo-perfusion and an indicator of reduced cardiac output the intensity of which is associated with symptoms of depression, muscle dysfunction and anemia. Fatigue is also an independent predictor of increased cardiac readmission and mortality rate in HF patients (Tsai et al., 2013). Fatigue can be explained by clinical factors such as age, anemia, poor sleep quality, decreased exercise capacity, dyspnea and psychosocial distress (Kessing, Denollet, Widdershoven, & Kupper, 2016). Fatigue and dyspnea are therefore multifactorial and can restrict daily performance and self-care and ultimately reduce quality of life (QoL) in the HF patient (Wang, Huang, Ho, &

Chiou, 2016).

In the pathophysiology of dyspnea and fatigue, the inabil- ity of the respiratory muscles to consume oxygen exceeds central hemodynamic defects, and given the alterations in the skeletal muscles (e.g. muscle atrophy, increased glyco- lytic type-II fibers or decreased mitochondrial enzymes) in HF, the question comes up as to how fatigue and dyspnea symptoms will respond to inspiratory muscle training (IMT) (Pozehl, Duncan, & Hertzog, 2008).

A study reported 39% of cardiac centers surveyed did not implement exercise rehabilitation for HF patients (Zwisler et al., 2016). Moreover, most severely impaired patients with an New York Heart Association (NYHA) class III/IV have limited physical activity and less adherence to conventional exercise training programs (Smart et al., 2013); for these reasons, home-based IMT programs supervised by nurses and other healthcare professionals have been recommended as a safe, flexible, and adjuvant treatment of pharmacologic inter- ventions in HF patients (Pihl, Cider, Strömberg, Fridlund, &

Mårtensson, 2011; Smart et al., 2013). Despite its underuse in clinical practice (Montemezzo et al., 2014), IMT therapy may be an alternative treatment modality for patients who cannot engage in center-based exercise training programs (Padula, Yeaw, & Mistry, 2009; Zwisler et al., 2016).

Several studies have supported the positive effects of IMT on respiratory strength, respiratory endurance (Montemezzo et al., 2014; Plentz, Sbruzzi, Ribeiro,

Ferreira, & Dal Lago, 2012; Ulbrich et al., 2016; Yamada et al., 2016), maximal and submaximal exercise capacity in HF patients (Montemezzo et al., 2014; Palau et al., 2014).

Furthermore, the advantages of IMT alone in patients with HF included improvements in the peak oxygen consumption (VO2), VO2 kinetics during recovery, ventilation /carbon dioxide ratio (VE/VCO2) slope (Cahalin & Arena, 2015;

Gayda, Ribeiro, Juneau, & Nigam, 2016), spirometric parameters (Adamopoulos et al., 2014), cardiac output (CO), stroke volume (SV), heart rate (HR) (Moreno et al., 2017), respiratory rate (RR), circulatory power, oxygen uptake efficiency, diaphragmatic velocity, peripheral muscle sympathetic nervous activity (Cahalin & Arena, 2015), the amelioration in the symptom of dyspnea (Wu, Kuang, & Fu, 2018), improved QoL and surrogate markers of disease severity (Palau et al., 2014).

In a clinical trial, aerobic training (AT) combined with resistance training (RT) and IMT led to an additional improvement in both peripheral and respiratory muscle weakness, cardiopulmonary function and dyspnea compared to AT alone (Laoutaris et al., 2013). Some studies have been conducted on the response of fatigue and dyspnea to exercise training in HF patients, and most of the findings on this subject have been contradictory, as the effectiveness of exercise training in reducing fatigue and dyspnea was not significant in two studies (Pozehl et al., 2008; Willenheimer et al., 2001). However, in a study by Bos¸nak-Güçlü et al. (2011), a 6-week IMT program improved fatigue and dyspnea in patients with stable HF.

Regarding the effectiveness of IMT in the management of HF patients, most studies have had small sample sizes (Adamopoulos et al., 2014; Bosnak-Guclu et al., 2011) and have assessed the effects of IMT on other clinical outcomes, such as inspiratory muscle strength and endurance, VO2, QoL and the 6-min walk distance (6MWD) test, and have reported contradictory results (Lin, McElfresh, Hall, Bloom, & Farrell, 2012; Plentz et al., 2012; Smart et al., 2013). However, in patients with HF with a preserved ejection fraction (HFpEF), IMT was found to have no effects in terms of the echocardiogram parameters of diastolic function and prognostic biomarkers (Palau et al., 2014). Other studies have reported the failure of IMT protocol in showing any improvement in endothelial function (Nicolodi et al., 2016), aerobic capacity (Sadek et al., 2018), respiratory function and the 6MWD (Cutrim et al., 2019).

Focusing on respiratory muscles abnormalities (Marco et al., 2013; Sadek et al., 2018) and varying outcomes such as respiratory and hemodynamic measurements (Cahalin &

Arena, 2015; Moreno et al., 2017), some studies have compared the benefits of the different intensities of IMT combined with AT and RT in HF patients (Smart et al., 2013).

The same authors also reported effects of IMT on dyspnea

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and autonomic activity in case–control studies (Marco et al., 2013). The real efficiency of the IMT has still not been established. Moreover, the devices that might result in improved efficiency have not been identified (de Abreu, Rehder-Santos, Minatel, dos Santos, & Catai, 2017; Paiva et al., 2015). Hence, it is necessary to identify IMT-ideal patient populations and the optimal durations, frequencies, workloads and the parameters required for it (Adamopoulos et al., 2014; Wu et al., 2018), in larger clinical trials (Lin et al., 2012).

Given the potential effects of IMT on the symptom management of HF patients, its inadequate application in the management of pathophysiologic manifestations of HF, the significance of the management of dyspnea and fatigue in home-based nursing practice (Padula et al., 2009; Perez- Moreno et al., 2014) and clinical trials (AbouEzzeddine et al., 2016; Ezekowitz et al., 2012; Perez-Moreno et al., 2014), the present study was conducted as a two-center study to determine the effects of IMT on the severity of dyspnea, fatigue and the NYHA functional classification in HF patients.

2 | M E T H O D S 2.1 | Study design

This was a prospective, randomized, controlled trial study.

2.2 | Setting and subjects

A total of 84 patients with HF referred to two cardiac rehabilitation hospitals in two teaching hospitals affiliated to the Lorestan University of Medical Sciences, in the west of Iran, between August 2015 and May 2016 were examined in this study.

The inclusion criteria consisted of having HF due to ischemic or dilated cardiomyopathy, age 18 and above, left ventricular ejection fraction (LVEF) ≤40%, NYHA functional classes II, III or IV, hemodynamic clinical stability and no changes in cardiac medications for at least the last 2 months and during the study. The patients with a cardiac pacemaker could enter the study 6 weeks after the implanta- tion of the pacemaker.

The exclusion criteria consisted of having unstable angina, complex arrhythmias, acute myocardial infarction or cardiac surgery over the past 3 months, uncontrolled hypertension, chronic metabolic, orthopedic-rheumatologic or infectious diseases, treatment with hormones and chemother- apy, a history of exercise-induced asthma or chronic kidney disease, being on hemodialysis, abuse of any substances and cognitive impairment, previously received cardiopulmonary

rehabilitation and any major non-cardiac problems that could adversely affect survival during the study.

Individuals with functional limiting determinants that might interfere with the performance of IMT and/or the maximal inspiratory pressure (MIP) measurement, such as unstable angina, complex arrhythmias, orthopedic-rheumatologic or infectious diseases and cognitive deficit and so on, were excluded from this study.

2.3 | Sampling

Based on two-sided α = .05, power = 0.8, and an effect size = 0.75, the sample size was determined as 40 patients for the comparison of the means between the two groups (Polit & Beck, 2004). This effect size was calculated based on the mean differences of dyspnea as a primary endpoint, between the IMT and sham groups in previous studies (Bos¸nak-Güçlü et al., 2011; Karadallı, Bos¸nak-Güçlü, Camcıoglu, Kokturk, & Türktas¸, 2016). The number of patients needed per group was 49 people to effectively assess differences in averages; the researchers obtained 98 participants with 49 participants in each group in antici- pation of drop-out participants (with an anticipated 25%

drop-out rate).

2.4 | Randomization

Prior to randomization, all patients' clinical assessments and echocardiographic measurements were done by a cardiolo- gist in each center. Patients were randomly allocated to either a treatment group (49 patients) receiving IMT or a control group (49 patients) receiving sham training for 6 weeks. Computer-generated random numbers were used for the stratified block randomization of the patients, with a block size of four and an allocation ratio of 1:1. To accom- plish the homogeneity of the groups, strata were created based on gender. An independent person not involved in this study possessed the computer-generated randomization.

The researcher who had collected the data before and after the IMT and the patients were unaware of the group allocations. At each center, the training, measurement and assessment of the patients were performed by cardiac rehabilitation specialist nurses (one nurse per center). The treatment and control groups were trained separately at different times and locations. None of the subjects had previously received cardiopulmonary rehabilitation.

2.5 | Outcome measures

The primary endpoint measurements included fatigue evaluated with the Fatigue Severity Scale (FSS) and dyspnea using the Modified Medical Research Council (MMRC)

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scale. Secondary endpoint measurement included HF symptoms based on the NYHA functional class.Before and after the training, dyspnea and fatigue perception, and NYHA functional classification were evaluated.

2.5.1 | Fatigue

Fatigue was evaluated using the Persian version of the FSS (Ghotbi, Nakhostin Ansari, Fetrosi, Shamili, & Choobsaz, 2014). The FSS is a nine-item self-administered question- naire that asks the patients to rate nine statements according to their level of agreement. Each item is scored from zero to seven (from “strongly disagree” = 0 to “strongly agree”= 7). A score of 36 (out of a maximum of 63) indi- cates significant fatigue (Krupp, Alvarez, Larocca &

Scheinberg, 1988). The qualitative content validity of the FSS has been confirmed in previous studies in Iran, and its test–retest reliability has been calculated as 0.78 to 0.95 (Ghotbi et al., 2014).

2.5.2 | Dyspnea and the NYHA functional classification

The severity of dyspnea during activity was assessed using the five-item MMRC dyspnea scale. The severity of dyspnea is graded from zero (no dyspnea during routine activities or strenuous exercise) to four (dyspnea during routine activities) in this scale. The patients were asked to read the descriptive statements in the scale and then choose a number that best matched their dyspnea (Bos¸nak-Güçlü et al., 2011).

The reliability of the scale was already confirmed in previous studies using the intra-class correlation coefficient, which has been reported as 0.82 both at baseline and at follow-up (Mahler et al., 2009). The MMRC scale has been used less often in previous studies conducted in Iran and its validity and reliability have not been determined. The validity of the MMRC scale was therefore determined in the present study using the face and qualitative content validity methods after implementing the views of heart, lung and nursing specialists and its reliability was calculated with an intra-class correlation coefficient of 0.8. The limiting symptoms (e.g. dyspnea, fatigue, or peripheral edema) and exercise tolerance were also registered through self-report based on the NYHA functional classification (Snyder, Van Iterson, & Olson, 2015).

2.6 | Intervention

2.6.1 | Measurement of MIP

The MIP was measured using a hand-held respiratory mouth pressure meter (Digital Manometer, ELKA, PM 15). After closing the nose with nose clips, the patients were trained to

breathe through the mouthpiece only during inspiration. The MIP values were measured in a standing position by a deep inspiration from the residual volume, and were expressed in cmH2O. At each supervised session, the MIP measurement was repeated at least within 1-min intervals, until three tech- nically satisfactory measurements were obtained. The highest value of the three measurements (with less than 5%

of difference) was used to define the MIP. The measurements were taken every week during the treatment by a blinded investigator. The MIP was measured as recommended by the American Thoracic Society/European Respiratory Society. The treating nurses measured the values of MIP and readjusted the training workloads.

2.6.2 | IMT protocol

Training was carried out using a pressure threshold loading device (POWER breathe Classic, IMT Technologies Ltd, Birmingham, UK). The device pressure was adjusted according to the MIP and its reliability was also demon- strated (Karadallıet al., 2016). Prior to beginning the IMT, the patients were familiarized with the threshold device and received practical instructions on efficient diaphragmatic breathing. The training workloads were then adjusted to lower loads, and the patients were instructed on how to maintain adequate inspiration and expiration when using the threshold IMT device. The IMT began once the patients had learnt how to maintain the workloads. The treatment group received IMT at 40% of the MIP and its training loads were adjusted to maintain 40% of the MIP weekly. The MIP was measured every week in supervised sessions, and 40% of the measured value was regarded as the new training workload.

The sham control group received IMT at a fixed workload of 10% of the MIP. Both groups trained 30 min per day (once a day), 7 days per week, for 6 weeks. Every 30-min session per day included 3-min sets of training, followed by short intervals of 1-min rest between the sets. Six sessions of the training were performed at home in both groups, and one session was supervised by a cardiac nurse at the rehabilitation center (one cardiac nurse in each center). To ensure the safety of the training, the patients' HR, blood pressure, oxygen saturation, and RR were monitored during the supervised session at the rehabilitation center, and the new workload was adjusted for the treatment group. There were seven supervised sessions overall (one during the familiari- zation period, and one weekly session for 6 weeks). The patients were encouraged to maintain diaphragmatic breathing for 10–15 breaths and to take 5–10 s of rest between their breaths. The patients were instructed to train in a sitting or half-sitting position when they had the least fatigue and dyspnea. They were also encouraged to maintain 25–30 breaths in each workload. They used nose clips in every

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training session and were instructed to inspire through a mouthpiece at the desirable workload.

The patients were followed up on the phone twice a week to check the correct performance of the exercises and potential problems or adverse effects during training, including nausea, headache, fatigue, muscle cramps, chest pain, signs of respiratory distress or hypercapnia and so on. These potential adverse effects were monitored either through self- report or by asking patients during their clinic visit. In cases where these signs/ symptoms appeared, the patients were advised to postpone their sessions until all signs and symptoms subsided. To record compliance, participants from both groups received a diary to register the time and days of all training sessions. The patients' IMT diaries were also checked every week during the sessions held at the rehabilitation center. The total number of minutes spent on training over the 6 weeks was calculated based on the patients' diaries.

The complete study protocol consisted of 42 daily training sessions completed over 6 weeks. The patients had been told not to change the pressure loads during the study period on their own, and were instructed not to take part in exercise programs or have physical activity more than the daily routine.

2.7 | Analysis of the results

All the continuous variables were expressed as mean

± standard deviation, and the non-normally distributed variables as median and interquartile range. Baseline compari- sons between the groups were performed using Student'st- test for the normally distributed variables (age, BMI, LVEF and MIP). The nominal and categorical variables (gender, disease etiology, NYHA class and medication history) were assessed using the Mann–WhitneyU, Fisher exact and Chi- squared tests. The normal distribution of the data was assessed using the Kolmogorov–Smirnov test. Wilcoxson's signed-rank test and the paired t-test were used to assess training-induced changes (before and after) within a particular group. Analysis of covariance (ANCOVA) was performed to compare the changes in the severity of fatigue, dyspnea and the NYHA functional class between the two groups and take account of the changes from the baseline values. The NYHA functional class was analyzed using McNemar's test. P-values

<.05 were considered statistically significant for all the tests.

Data were analyzed in SPSS 16 (SPSS Inc., Chicago, IL, USA).

2.8 | Ethics considerations

The study was approved by the regional Ethics Committee of University of Medical Sciences (ID: LUMS.REC.1395.106) and performed in accordance with the Declaration of Helsinki.

Participants were notified concerning the training and its possible risks. Informed consent was obtained from all the

participating patients. The study was registered at the Iranian Registry of Clinical Trials (ID: IRCT2016071324080N2) (http://www.irct.ir/fa/).

3 | R E S U L T S

A total of 260 patients with HF were screened between August 2015 and May 2016, 162 of whom were ultimately excluded for various reasons (Figure 1), and the remaining 98 patients were randomly assigned to the treatment and control groups. Ultimately, 84 patients (40 women and 44 men), with LVEF =32.45 ± 5.71% completed the study, including 42 in the treatment group and 42 in the control group. A total of 42 (50%) patients were in NYHA class III, and 10 (11.9%) in NYHA class IV. All the patients were receiving optimal medical therapies, including angiotensin-converting enzyme inhibitors (ACEs), angiotensin II receptors, beta-blockers, diuretics and digoxin. No significant alterations were made to the medications in the groups during the study. All the patients had tolerated the IMT with no side-effects during the treatment and assessment. No significant changes were observed or reported in vital signs during the adjustment of the new workload in the supervised or follow-up sessions.

Respiratory muscle weakness (MIP <70% of the predicted) (Kawauchi et al., 2017), was observed in 27 patients (64.28%) in the treatment group and 24 patients (57.14%) in the control group. Over the course of the study, the treatment group had a mean 39.6 ± 6.35% of MIP, but the control group had a fixed 10% of MIP. Adherence to the treatment program was high in both groups and 100% of them had followed the treatment program to the end. No hospitalizations or deaths occurred during the study due to worsening HF. No significant differences were observed between the two groups in terms of the amount of time spent on the IMT, which was 3220.46 ± 55.25 min for the treatment group (96.25 ± 7.15% of the expected) and 3360.66

± 35.8 min for the control group (95.27 ± 4.25% of the expected); (P< .05).

3.1 | Baseline characteristics

No significant differences were observed between the two groups in terms of their baseline demographic details, including age, gender, NYHA functional class, BMI, medications, smoking, vital signs, HF etiology, diagnosis time and comorbidities (Table 1) (P> .05). The etiology of HF was predominantly ischemic in both groups. The BMI was over 25 kg/m² in 25 patients in the treatment group (59.52%) and 23 in the control group (54.76%). Duration since diagnosis was 1–5 years in most patients. A total of 40% of the participants had hypertension, diabetes and COPD as comorbidities, and the two groups were

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statistically similar in terms of the LVEF, dyspnea, fatigue and NYHA functional classification (P> .05) (Table 1).

3.2 | Fatigue

The between-group analysis showed a significant difference in the perception of fatigue; in the treatment group, the mean fatigue

reduced after the intervention compared to before (P< .001), but in the control group, the mean fatigue score somewhat increased after the intervention compared to before. The within-group analysis also showed a significant reduction in the perception of fatigue in the treatment group, but no such effects were observed in the control group. A significant group*time interaction was observed for fatigue (P< .05); (Table 2).

F I G U R E 1 Consolidated Standards of Reporting Trials(CONSORT) flow diagram

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3.3 | Dyspnea

The between-group analysis showed a significant difference between the two groups in the severity of dyspnea; in the treatment group, the mean severity of dyspnea reduced after the intervention compared to before (P < .001), but in the

control group, the mean severity of dyspnea somewhat increased after the intervention compared to before. The within- group analysis also showed a significant reduction in the severity of dyspnea in the treatment group, but no such effects were observed in the control group. A significant group*time interaction was observed for dyspnea (P< .05); (Table 2).

T A B L E 1 Baseline demographic characteristics of treatment and control groups

Characteristics

Treatment group (n= 42)

Control group (n= 42)

P value

Age, years 55.97 ± 9.43 57.28 ± 9.06 .52^a

Male/female, n 23/19 21/21 .66^b

BMI, kg/m² 25.6 ± 5.2 25.8 ± 4.1 .54^a

MIP, cmH₂O 59.01 ± 42.47 61.21 ± 72.33 .61^a

NYHA, II/III/IV,n 15/23/4 17/19/6 .86^c

LVEF, % 33.7 ± 6.1 32.5 ± 4.4 .34^a

Disease etiology (DCM/ICM), n(%)

29/13 (69.04/30.95) 31/11 (73.80/26.20) .81^c

Smoking, pack-years 28.79 ± 16.01 30.73 ± 44.21 .76^a

Smoking (non/ex-smoker), n(%)

20/21 (47.61/50) 19/23 (42.23/54.76) .18^a

Vital signs

SBP, mmHg 132.3 ± 6.3 134.6 ± 7.8 .44^a

DBP, mmHg 81.8 ± 10.1 81.4 ± 4.1 .26^a

HR, bpm 68 ± 16.2 70 ± 26.3 .81^a

Medicationn(%)

ACEI 39 (92.85) 42 (100) .24^c

ARB 12 (28.57) 10 (23.80) .23^c

Beta-blockers 27 (64.28) 24 (57.14) .82^c

Diuretics 32 (76.19) 32 (76.19) .99^c

Digoxin 9 (21.42) 12 (28.57) .61^c

Calcium antagonist 15 (35.7) 15 (35.7) .99^c

Time from diagnosis, years n(%)

.63^c

1 to 5 years 24 (57.14) 29 (69.04)

5 to 10 years 13 (30.95) 9 (21.42)

>10 years 5 (11.90) 4 (9.52)

Other morbidities,n(%)

Hypertension 19 (45.23) 19 (45.23) .99^c

Dyslipidemia 8 (19.04) 10 (23.80) .22^c

Diabetes 18 (42.85) 16 (38.09) .65^c

COPD 18 (42.85) 17 (40.47) .78^c

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers;

BMI, body mass index; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure;

DCM, dilated cardiomyopathy; HR, heart rate; ICM, ischemic cardiomyopathy; LVEF, left ventricular ejection fraction; MIP, maximal inspiratory pressure; NYHA, New York Heart Association; SBP, systolic blood pressure.

Note:Quantitative variables are presented as mean and standard deviation (mean ± SD).

aPvalues reported based on independentt-test.

bPvalues reported based on Fisher exact test.

cPvalues reported based on Chi-square test.

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3.4 | NYHA functional classification

The analysis showed a significant improvement in the NYHA class in the treatment group, but no such improvements were observed in the control group (Table 2). This result was also confirmed by the McNemar test, and the NYHA functional class improved to class II (P= .003) and class III (P= .048); (Table 3) (Figure 2).

4 | D I S C U S S I O N

Compared to the sham training program, a home-based 6-week IMT program led to significant improvements in the perception of fatigue, the severity of daily dyspnea and the NYHA functional classification in patients with classes II, III and IV HF in this study. IMT led to significant improvements in respiratory muscle strength, exertional dyspnea, exercise capacity and blood flow in the extremities during exercise and rest in HF patients (Chen et al., 2016).

Laoutaris et al. (2016) concluded that the impact on the respiratory muscles in patients with HF would be greater on the capacity to carry out work than on strength.

In the present study, most patients had inspiratory muscle weakness, and almost half of them had COPD. Inspiratory muscle weakness or respiratory fatigue resulted in dia- phragm ischemia, and decreased mechanical efficiency.

However, a study indicated that following 8 weeks of IMT, inspiratory muscle strength increased by 78% (Moreno et al., 2017). Cutrim et al. indicated that a low-intensity IMT (30%

MIP) three times per week for 12 weeks could improve cardiac autonomic modulation and exercise tolerance of patients with COPD (Cutrim et al., 2019). A systematic review study showed that, compared to the control group, although IMT improves exercise performance in patients with normal inspiratory muscle strength, it leads to a greater improvement in the maximal and submaximal exercise capacity in patients with respiratory muscle weakness (Montemezzo et al., 2014).

The greater effect of IMT on outcomes in patients with respiratory muscle weakness (Montemezzo et al., 2014;

Smart et al., 2013) can be explained by noting that exercis- ing these muscles through IMT can decrease anaerobic metabolism, which delays respiratory muscle fatigue and metabo-reflex and improves minute ventilation and maximal oxygen consumption (Montemezzo et al., 2014). Sympa- thetic outflow-induced diaphragmatic respiratory muscle weakness and fatigue increased blood pressure and reduced arterial blood flow to the extremities. Nevertheless, one study found that IMT can reduce the systolic and diastolic blood pressure in patients with hypertension by reducing the peripheral sympathetic activity (Ferreira et al., 2013). While suggesting the need for the assessment of respiratory muscle TABLE2Effectsofinspiratorymuscletrainingonfatigue,dyspnea,NYHAfunctionalclassification Characteristics

Treatmentgroup(n=42)Controlgroup(n=42) BeforeAfter Mean difference±SD Group difference,PBeforeAfter Mean difference±SD Group difference,P Treatment effect,P Fatigueseverityscale(0–63), mean±SD

43.36±8.5028.95±9.11−14.41±6.35<.001a 40.64±10.8941.47±10.670.83±2.19.018a <.001b MMRCscale(0–4),mean ±SD 2.63±0.791.38±0.66−1.25±0.21<.001a 2.19±0.892.28±0.940.09±0.03.036a <.001b MMRCscale,median (interquartilerange)

3(1)2(1)<.001c2(1)2(1).036c<.001d NYHA(2–4),mean±SD2.73±0.52.10±0.6−0.63±0.05.001a 2.73±0.82.65±0.5−0.08±0.05.27a .003b Abbreviations:MMRC,ModifiedMedicalResearchCouncil;NYHA,NewYorkHeartAssociation;SD,standarddeviation. aPvaluesreportedbasedonpairedStudent'st-test. bPvaluesbetweengroupsreportedbasedonindependentt-test. cPvaluesreportedbasedonWilcoxson'ssigned-ranktest. dPvaluesbetweengroupsreportedbasedonMann–WhitneyU-test.

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weakness and fatigue (Montemezzo et al., 2014) as a potential prognostic factor in HF patients (Marco et al., 2013), these results can also be used in fatigue and blood pressure management using IMT in HF patients.

Consistent with the results of previous studies (Cahalin & Arena, 2015; Karadallıet al., 2016), IMT at 40%

of MIP, could decrease severe fatigue and dyspnea perception in the present study. It seems that the effects of IMT depend on the load of MIP adjusted, the frequency, and the duration of the intervention or patients' characteristics.

A study by Laoutaris et al. (2007) showed that no significant effect on HR, exercise capacity and dyspnea was observed in the sham group (15% MIP). A systematic review and meta-analysis showed that high-intensity IMT at 60% of MIP, six times per week and for 12 weeks, could result in a significant improvement in dyspnea, walking distance and inspiratory muscle strength (Sadek et al., 2018). The beneficial effect of high-intensity IMT may be due to a greater improvement in endothelial function, increasing respiratory

muscle mass, and improving oxygen metabolism (Cahalin &

Arena, 2015; Sadek et al., 2018).

An important result obtained in the present study was the decrease in the severity of fatigue following IMT. Improved peripheral blood flow and functional capacity following IMT can help reduce fatigue (Bos¸nak-Güçlü et al., 2011).

A reduction in fatigue can then allow an improvement in daily activities (Adamopoulos et al., 2014), wellness and roles within society (Conley et al., 2015). In a study conducted by Busnak-Gucle, although a similar reduction was observed in fatigue within the control and treatment groups in HF patients following IMT, a higher IMT workload had no greater effectiveness than a lower workload, and the authors argued that lower workloads can also have therapeu- tic effects on fatigue (Bos¸nak-Güçlü et al., 2011). In line with the present findings, a study conducted by Ray et al., found that combined inspiratory and expiratory muscle training (EMT) improved fatigue in patients with multiple sclerosis in the intervention group, but had no effects or even worsened the condition in the control group (Ray, Udhoji, Mashtare, & Fisher, 2013).

Furthermore, expiratory muscle weakness, inspiratory muscle weakness and poor inspiratory muscle endurance (IME) in HF led to a maladaptive breathing pattern or a shorter expiratory time, and prolonged the ratio of inspiratory time to total breath time (Ti/Ttot). Hence, altering the Ti/Ttot via EMT and IMT has the potential to significantly improve the pathophysiologic symptoms of HF such as fatigue and dyspnea (Cahalin & Arena, 2015). A study found that IMT was more beneficial than EMT (Tout, Tayara, & Halimi, 2013). Many of the beneficial effects of EMT and IMT that are observed in patients with HF are due to the improvements in pulmonary perfusion or improvements in pulmonary artery pressure (PAP), pulmonary vas- cular resistance (PVR), and the VE/VCO2slope (Cahalin &

Arena, 2015). Moreover, it is possible that, IMT has the potential to decrease exercise oscillatory ventilation (EOV) based on the pathophysiologic mechanisms such as (a) reducing the chemosensitivity to PaCO2and PaO2, and (b) improving right ventricle to pulmonary circulation cou- pling (Cahalin et al., 2013).

T A B L E 3 Number of patients (%) in the treatment and control groups according to NYHA

Characteristics Treatment group (n= 42) Control group (n= 42)

NYHA Before After Before After

II 15 (35.71) 21 (50)* 17 (40.47) 16 (38.09)

III 23 (54.76) 18 (42.85)** 19 (45.23) 20 (47.61)

IV 4 (9.52) 3 (7.14) 6 (14.28) 6 (14.28)

Abbreviation: NYHA, New York Heart Association.

*P= .003.

**P= .048 vs baseline (based on McNemar's test).

F I G U R E 2 New York Heart Association (NYHA) functional class changes before and after inspiratory muscle training (IMT) in the treatment and control groups

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Other studies have also regarded fatigue as a dimension of the QoL or an indicator of exercise capacity. In line with the present findings, Laoutaris et al. (2013) also found that, compared to aerobic exercise alone, the combination of AT and RT and IMT can lead to a significant improvement in the QoL in HF patients. Other studies have shown that, due to the inadequate duration and severity of training, IMT has no significant effects on QoL and symptoms of HF such as fatigue (Lin et al., 2012; Sbruzzi, Dal Lago, Ribeiro, &

Plentz, 2012). Fatigue is multifactorial and the fatigue- reducing effects of IMT (Ferreira et al., 2013) should be investigated with regard to the factors associated with fatigue, such as depression, pain and quality of sleep (Fink et al., 2012).

Dyspnea can be considered another dimension of symptom management in terms of QoL (Seo et al., 2016). In line with the present findings, a trial study found that the addition of high-intensity IMT to AT had positive effects in terms of muscle weakness, dyspnea and cardiopulmonary function.

Improvement in dyspnea can be caused by improved inspiratory muscle strength and endurance. In a study conducted by Marco et al., the patients showed significant improvements in inspiratory muscle strength and endurance following 4 weeks of high-intensity IMT, and the scores obtained on the MMRC scale improved in the high-intensity IMT group by the end of training (Marco et al., 2013).In a study conducted by Adamopoulos et al., to improve pulmonary ventilation, combined AT/IMT led to significant improvements in dyspnea and QoL in HF patients compared to AT alone (Adamopoulos et al., 2014). Studies conducted on HF (Saglam et al., 2015) and other chronic diseases have shown that IMT reduces dyspnea during routine activities (Karadallı et al., 2016) by improving the functional and maximal exercise capacity (Saglam et al., 2015).

In the study by Busnak-Gucle et al., the between-group analysis showed that IMT has no dyspnea-reducing effects according to the Borg Scale, but in line with the present findings, that study also showed that IMT is effective in reducing dyspnea according to the MMRC scale. These results show that the effect of IMT on dyspnea can be influenced by the dyspnea assessment scale used (Bos¸nak- Güçlü et al., 2011). Also a trial study found practicing diaphragmatic breathing was feasible and showed positive effects on activity but not by reducing dyspnea. The differences in results among studies point to the need for a consistent tool of dyspnea in patients with HF. Furthermore, a measure is needed that would capture three dimensions of dyspnea recommended by the American Thoracic Society:

burden of dyspnea, sensory-perceptual experience and affec- tive distress (Seo et al., 2016).

In the present study, the NYHA functional classification was taken as an important outcome. Other studies have

focused mainly on the LVEF and less on signs and symptoms, especially in functional classes III and IV (Montemezzo et al., 2014), such that Adamopoulos et al.

(2014) found that both combined aerobic exercise and IMT and aerobic exercise alone can improve LVEF and NYHA functional class in patients with moderate HF. While empha- sizing the importance of the duration of the intervention, Palau et al. (2014) found that a 12-week IMT program had positive effects on classes III and IV, HF patients with HFpEF. Kawauchi et al. (2017) found that only moderate- intensity IMT improves expiratory muscle strength and the NYHA functional class in classes II and III patients with HF reduced ejection fraction (HFrEF). Given that in the review of literature and the present study, the greatest improvement was observed in classes II and III patients, it can be said with some caution that IMT is effective in improving the NYHA functional class in HFpEF and HFrEF patients; however, this finding requires further studies.

5 | L I M I T A T I O N S

The present study screened mostly the active patients who were willing to take part in the rehabilitation program. The number of class IV patients was also lower than the number of classes II and III patients, which limits the generalizability of the results to all HF patients, especially those who did not take part in rehabilitation programs and also class IV patients who are more prone to irreversible failure, re- hospitalization and transplantation. Future studies are recommended to examine the effects of IMT on the health outcomes in class IV patients with larger sample sizes. Other limitations of the study include the fact that respiratory diseases affect the response to IMT, but since COPD is a com- mon comorbidity (Lin et al., 2012), these diseases could not be assessed and were excluded from the study. Future clinical trials should consider patients with and without inspiratory muscle weakness.

6 | C O N C L U S I O N A N D A P P L I C A T I O N S

The present findings showed that moderate-intensity IMT can help with the management of symptoms such as fatigue and dyspnea and improve NYHA functional classes II, III and IV HF patients. By teaching IMT, cardiac rehabilitation nurses can help HF patients with the safe and effective management of their symptoms, at home. However, such home- based IMT training may be fully effective when directly supervised by a nurse or guided by telemonitoring. Given that the present study did not assess patients in the acute phase of the disease, future studies are recommended to

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examine the short- and long-term effects of IMT with different modalities on the symptoms of HF in patients hospital- ized in intensive care units.

A C K N O W L E D G M E N T S

The authors would gratefully acknowledge the assistance of Babak Baharvand Ahmadi, Professor of Cardiology at Lorestan University of Medical Sciences. The authors would also like to thank all of the participants who participated in this study.

C O N F L I C T O F I N T E R E S T

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A U T H O R C O N T R I B U T I O N S

M.G. and M.S. conceived and designed the study. M.G. and A.H. H.P. contributed to development of the research protocol and data collection tools. M.G., A.H. H.P. and M.B. contributed to the acquisition and analysis of the data for the work. M.G. and M.B. contributed to the interpreta- tion of the data. M.G. and A.H. H.P. wrote the first draft. All authors critically reviewed the manuscript and approved the version for submission.

O R C I D

Mohammad Gholami https://orcid.org/0000-0001-5553- 2651

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How to cite this article: Hossein Pour AH, Gholami M, Saki M, Birjandi M. The effect of inspiratory muscle training on fatigue and dyspnea in patients with heart failure: A randomized, controlled trial.Jpn J Nurs Sci. 2020;17:e12290.https://doi.org/

10.1111/jjns.12290