Home-based inspiratory muscle training in adults with cystic fibrosis: a case series report.
Increased work of breathing (WOB) associated with cystic fibrosis (CF) pulmonary disease contributes to exercise intolerance secondary to dyspnea and decreased ventilatory efficiency. (1-3) A significant portion of this WOB falls on the inspiratory muscles, which play a role in the genesis of dyspnea and altered breathing patterns. (4-6) As a result, excess WOB imposed on these muscles could indirectly limit exercise capacity in CF. (1) Methods to maximize exercise tolerance in CF should be investigated as aerobic fitness is linked to mortality. (7) Specific inspiratory muscle training (IMT) may alleviate imbalances between the WOB and the inspiratory muscles and subsequently improve exercise performance.
Dyspnea, quality of life, and symptom-limited functional exercise capacity can be improved with IMT in chronic obstructive pulmonary disease (COPD) which shares pathologic similarities with CF. (8) Enhancing inspiratory muscle strength (IMS), as represented by maximal inspiratory pressure (MIP), may be favorable over inspiratory endurance training in COPD, (8) however, only 4 studies to date have investigated IMT alone in CF with only one specific to the adult population. (9-12) In all cases, IMT increased inspiratory muscle function, (9-12) however, improved pulmonary function and exercise capacity occurred in only 2 of these studies. (11,12) These studies suggest that IMT can improve inspiratory muscle function in CF but the transference to clinically relevant outcomes is unclear. The effect of IMT on dyspnea and quality of life was not investigated adequately and its impact on functional exercise capacity has not been examined in CF.
As individuals with CF transition into adulthood, the demands of care are difficult to coordinate with external responsibilities. (13) Burdensome therapies can result in poor adherence, detract from established treatments, and potentially worsen quality of life. (14) Most IMT protocols are demanding and require 30 minutes of training on most days of the week with benefits reversing upon cessation of training. Implementing such protocols in the clinical or research settings requires careful planning in the CF population as the burden of care is already high. A home-based protocol is a clinically relevant method to prescribe IMT in adults with CF provided it can result in meaningful outcomes. The purpose of this case series was to describe the feasibility and potential efficacy of a home-based IMT program to increase IMS, pulmonary function, and functional exercise capacity in adults with stable CF.
A prospective repeated measures design was used and approved by the Institutional Review Boards of the University of Pennsylvania and Rutgers, The State University of New Jersey (formally the University of Medicine and Dentistry of New Jersey). Informed consent was obtained prior to enrollment and the rights of all subjects were protected. Individuals (age [greater than or equal to] 18 yrs.) with stable CF were recruited from our adult CF program during routine outpatient visits using a sample of convenience. The diagnosis of CF was confirmed through prior genetic and/or sweat chloride testing. Individuals were considered to be stable if their current forced expiratory volume in one second ([FEV.sub.1]) was within 10% of baseline and they were free of signs and symptoms of a pulmonary exacerbation. Exclusion criteria were: current smokers, pregnancy, history of a spontaneous pneumothorax or current unresolved pneumothorax, acute orthopedic condition that would interfere with testing, recent thoracic or abdominal surgery, neuromuscular disease, perforated eardrum, systemic corticosteroids use (> 10 mg/day), uncontrolled diabetes, and heart failure. All measurements of pulmonary function, IMS, and functional exercise capacity occurred on the same day as a baseline and were repeated within one week of completing the intervention.
The [FEV.sub.1], forced vital capacity (FVC), the [FEV.sub.1] to FVC ratio ([FEV.sub.1]/FVC), and mid-expiratory flow rates ([FEF.sub.25-75%]) were measured as part of routine care by a licensed respiratory therapist certified in pulmonary function testing (PFT) according to standard guidelines. (15) The results from eligible consenting volunteers were retrieved from the medical record and expressed as both absolute values and percent of predicted according to Hankinson et al. (16) Change in the percent of predicted [FEV.sub.1] (%[FEV.sub.1]) was used to determine the outcome of IMT on pulmonary function.
Inspiratory Muscle Strength
Maximal inspiratory pressure at the mouth was measured using a handheld mouth pressure meter (MicroRPM[R] (RPM01), CareFusion Ltd., San Diego, CA) according to guidelines from the American Thoracic Society. (17) Maximal inspiratory pressure is a valid and reliable measure representing global IMS and is frequently used in the literature. (17-19) Measurements were recorded through a laptop interface and associated software (PUMA[R] (PU1000), CareFusion Ltd., San Diego, CA, USA). Maximal inspiratory pressure was defined as the maximum pressure sustained for one second, as it can demonstrate better reproducibility than peak pressure. (17) A thorough explanation of the procedure was provided and the technique demonstrated prior to testing. Subjects sustained a maximal inspiratory maneuver for at least 2 seconds from residual volume through a flanged mouth piece connected to the mouth pressure meter. A small leak was present in the inspiratory circuit to minimize the effect of the buccal muscles. Nose clips were not worn. Each subject was allowed 2 practice trials after which the best of 3-5 tests with less than 10% variability was recorded for analysis. Consistent verbal encouragement was provided during each test to help ensure maximal effort. Values were recorded both in cm [H.sub.2]O (MIP) and as percent of predicted (%MIP). (20)
Functional Exercise Capacity
The six-minute walk test (6MWT) was performed according to standard guidelines by a licensed physical therapist with extensive experience implementing this test. (21) All subjects were familiar with the 6MWT through routine care and standardized instructions and feedback were provided during testing. Peripheral oxygen saturation (Sp[O.sub.2]) was documented at rest and at peak exercise during the test along with dyspnea and perceived exertion using the Borg Scale. (22,23) Heart rate, blood pressure, and respiratory rate were monitored during testing to ensure physiologic stability but not included in the analysis. No subject required supplemental oxygen during the test and all subjects were able to walk for the entire duration without rest. The distance completed in 6 minutes (6MWD) served as the primary outcome measure to represent functional exercise capacity.
Subjects were instructed to refrain from making changes in their current exercise or airway clearance programs while performing a 6-week unsupervised IMT program at home using a commercially available threshold trainer (PowerBreathe, Caiam Ltd., Southam, UK). Threshold-IMT can increase IMS in pulmonary populations and was selected for its ability to control the inspiratory load making it suitable for home-based training. (8) The PowerBreathe[R] is a plastic handheld device with a mouthpiece and internal calibrated spring-loaded one-way valve. Subjects are required to generate and maintain the prescribed "threshold" inspiratory pressure for inhalation to occur. Exhalation is unimpeded. Target training intensity was set at 50% to 60% of the baseline MIP recorded but adjusted to tolerance if needed. Intensity remained constant during the intervention period and was not progressed. The appropriate level of resistance was set on the device according to manufacturer's guidelines. Training was performed 30 minutes per day, 6 days per week as tolerated. Subjects were instructed to perform single inspiratory repetitions from functional residual capacity to total lung capacity during each session. Individual repetitions were separated by brief rest periods based on subject tolerance; however, the total number of repetitions per session was not recorded. The training protocol was based on current literature in COPD and CF and has been suggested to improve measures of inspiratory muscle function. (8)
Each subject was instructed in the IMT protocol and demonstrated proper technique prior to entering the intervention period. Written instructions were provided and adherence was documented with a daily training log. Compliance rates were calculated as the total number of completed training minutes divided by the total prescribed minutes. Subjects were monitored via telephone every other day during week one followed by weekly calls for the remainder of the 6-week training period. Subjects were excluded from final data analysis if changes needed to be made to their medical management or in the presence of a pulmonary exacerbation during the intervention period. The occurrence of adverse events was recorded during the calls and the intervention was reviewed to help ensure appropriate training.
Data analysis was performed using IBM SPSS statistical software (v.21). Descriptive statistics for baseline demographics were reported for the participants. Normality of data was assessed with the Shapiro-Wilk test. Paired t-tests were used to assess for within group changes in the primary outcome measures pre- and postintervention. Results are reported as mean (SD) and statistical significance was set at [alpha] = 0.05. Individual subject changes were reported and analyzed in case series format.
Five adults with stable CF participated in this study and completed all testing of the primary outcome variables. Subject characteristics are summarized in Table 1 and the individually prescribed IMT protocols in Table 2. One participant (subject B) reported a compliance rate of 54% due to time constraints and was excluded from the final analysis. Individual and group changes in the primary outcome variables were evaluated in the remaining 4 subjects with a mean compliance rate of 92%. No adverse events were reported.
The individual and group results for the primary outcome measures are displayed in Table 3. Individual subject responses for peripheral oxygen saturation, dyspnea, perceived exertion, and distance during the 6MWT are illustrated in Table 4. As a group, there was a significant increase in mean MIP and %MIP after the training period increasing from 100.0 (34.2) cm [H.sub.2]O to 122.8 (38.0) cm [H.sub.2]O and 104.3 (20.9) % to 129.0 (23.1)% respectively (p = 0.009). There were no significant changes in %[FEV.sub.1] or 6MWD after training within the study group as compared to baseline. Figure 1 illustrates the relative percent of change in the primary outcome measures for each individual included in the final data analysis. Maximal inspiratory pressure increased in all subjects after training. In 3 subjects with normal IMS at baseline (%MIP > 100%), there was no change in %[FEV.sub.1] or the 6MWD. However, one individual (subject D) with decreased MIP at baseline (MIP = 60 cm [H.sub.2]O; %MIP = 76%) demonstrated a 10% increase in 6MWD (387.1m to 425.81m) and a 25% increase in %[FEV.sub.1] (44% to 55%) after training.
The observations in this case series suggest that home-based IMT may enhance IMS but have limited transference to functional exercise capacity and pulmonary function in adults with stable CF. Though feasible, the implementation of IMT was hindered by recruitment difficulty. Primary barriers to participation were the additional burden and uncertain benefit of IMT which are known to negatively influence adherence in CF. (14) However, one subject in our case series appeared to respond to IMT with improved pulmonary function and functional exercise capacity. Factors explaining this individual response and possible mechanisms of action should be discussed as benefits of IMT may outweigh its burden in select adults with CF.
Increased inspiratory work in CF is evidenced by an elevated tension-time index of the inspiratory muscles (TT). (5,24) This elevated TT results from an increased inspiratory pressure required per breath ([P.sub.br]) relative to MIP and is accompanied by a decreased inspiratory duty cycle. (5,24,25) These altered breathing patterns are theorized to protect against inspiratory fatigue and may compromise ventilatory efficiency. (5) Dyspnea perception also intensifies as the [P.sub.br]/MIP ratio increases. (4) A combination of dyspnea and/or altered breathing patterns could feasibly limit exercise tolerance in CF. The increased MIP observed in our subjects likely resulted in a decreased [P.sub.br]/MIP ratio. The resultant effect on breathing pattern is unclear; however, subject D demonstrated a 10% increase in the 6MWD without a concurrent increase in dyspnea (see Table 4). It is plausible that dyspnea relief resultant from IMT transferred to improved symptom-limited performance in this case.
[FIGURE 1 OMITTED]
In 1982, Asher et al (9) demonstrated small increases in inspiratory muscle endurance and IMS after 4 weeks of flow-based IMT without improvement in exercise capacity. De Jong et al (10) evaluated a 6-week training program at 40% MIP and demonstrated a 35% increase in inspiratory muscle endurance but no effect on IMS, dyspnea, exercise, or quality of life. In contrast, both Enright (11) and Sawyer and Clanton (12) suggested that IMT can enhance pulmonary function and exercise capacity. The higher intensities used by these later authors could explain this discrepancy as IMS training may be advantageous in pulmonary disease. (8) Increased IMS at higher intensities may have influenced the TT, as described above resulting in decreased dyspnea and improved breathing patterns to explain the observed ergogenic effects. However, Sawyer and Clanton (12) anecdotally noted "increased sputum production" associated with their protocol and the intervention used by Enright et al (11) has been shown to aid in sputum mobilization. (26,27) Enhanced secretion removal associated with IMT maneuvers may have contributed to improved pulmonary function and exercise tolerance in these studies as well as subject D in our case series.
Dyspnea-relief, enhanced breathing patterns, and facilitated airway clearance are plausible benefits of IMT in adults with CF. However, the conflicting literature and lack of response observed in 3 of our 4 subjects, questions the utility of IMT in the general CF population. In contrast, IMT is well-researched in COPD with promising results for IMS training to enhance functional exercise capacity; however, baseline inspiratory muscle weakness may be a prerequisite. (8) The existence of this impairment in adults with CF is questionable. Studies suggest IMS may be preserved in CF due to the chronically elevated work of breathing. (28-30) However, the subjects in these studies were heterogeneous in terms of pulmonary involvement, nutritional status, and hyperinflation which can each influence inspiratory muscle function. (31-33) Underrepresentation of subjects with advanced lung dysfunction may skew results and distort the degree of inspiratory muscle dysfunction in CF. Indeed, decreased MIP, as low as 23% of predicted, has been shown in the CF literature suggesting weakness may exist in select individuals. (34,35) Baseline weakness may explain the isolated benefits seen in this case series.
Inspiratory demands during exercise are not believed to reach a threshold that limits performance in healthy individuals. Though excess inspiratory work is evident in CF, this demand may be within the capacity of the inspiratory muscles in the absence of weakness. As observed in Table 3 and Figure 1, all subjects in this case series demonstrated improved IMS after IMT. However, MIP values were above 80 cm [H.sub.2]O in 3 of these subjects and could rule out clinically significant weakness. (17) Caution should be taken when making this observation as specific criteria for weakness in CF have not been established. Still, IMS may not have contributed to dyspnea, breathing patterns, and airway clearance in these 3 cases. Interestingly, only subject D with apparent weakness of the inspiratory muscles responded to IMT with a 38.7m increase in the 6MWD, exceeding the minimal important distance identified in COPD. (36) This response is in agreement with the COPD literature where MIP [less than or equal to] 60 cm [H.sub.2]O may identify candidates for IMT. (8)
Subject characteristics may influence the efficacy of IMT in CF. Nonpulmonary factors primarily limit exercise performance in mild CF lung disease. (37) This fact would explain the lack of response in subjects A and C, who had minimal pulmonary dysfunction. Benefits of IMT may be limited to individuals with moderate or severe CF lung disease where inspiratory demands are high; however, subject E did not respond to IMT even in the presence of severe disease ([FEV.sub.1] = 23%). Multiple factors associated with CF can negatively influence the inspiratory muscles including nutritional status and hyperinflation. (33) Specifically, a body mass index below 20 kg/[m.sup.2] has been associated with lower MIP in adults with CF. (31) Body mass index (BMI) was above this threshold in all subjects with apparently normal IMS (see Table 1). The maintenance of BMI may have preserved IMS in subject E. In the absence of weakness, these muscles did not likely limit functional exercise capacity in this case even in advanced lung disease. In contrast, malnutrition (BMI < 20 kg/[m.sup.2]) may have influenced IMS in subject D decreasing it to a level that was responsive to IMT in the presence of moderate lung disease.
Functional exercise capacity decreased in 2 subjects after the intervention period. The specific cause for this finding is unclear though it does not appear to be a negative result of training. The minor 4% decrease in subject C is likely explained by normal testing variability. However, the 10% decrease seen in subject E deserves attention. The present protocol was implemented in an outpatient CF clinic and subjects were undergoing routine care in addition the IMT. The use of supplemental oxygen in this subject was being discussed given the severity of lung disease. The psychosocial impact of oxygen use likely influenced the 6MWT performance rather than a negative effect from training.
The results of this case series fulfill its primary purpose though obvious limitations exist. The observed findings are only intended to promote discussion on the potential efficacy of IMT in CF. Cause and effect cannot be established. This study did not measure other aspects of inspiratory muscle function such as endurance and work capacity that may be affected in CF. (31,35,38) The noted increases in MIP suggest a strengthening effect occurred; however, the effect of the current protocol on inspiratory endurance is unknown. Future research on IMT should compare alternate protocols and aspects of muscle function in CF to determine their effect on exercise capacity. Finally, the impact of hyperinflation was not studied in this sample and may influence the effect of IMT. We plan to further investigate these factors in subsequent studies.
The results of this project highlight the importance of subject selection when considering IMT in adults with CF given its associated burden and unknown efficacy. The therapeutic role of IMT to improve functional exercise capacity may be limited to select individuals with CF and decreased IMS at baseline may identify appropriate candidates. Prospective randomized control trials are needed to determine the therapeutic role of IMT in individuals with CF.
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Robert L. Dekerlegand, PT, MPT, CCS ; Denis Hadjiliadis, MD, MHS, FRCP ; Mary Jane Myslinski, PT, EdD ; Douglas Holsclaw, MD ; Marianne Ferrin, CRNP 
 Rutgers, The State University of New Jersey, School of Health Related Professions, Stratford, NJ
 University of Pennsylvania, Adult Cystic Fibrosis Program, Philadelphia, PA
 Rutgers, The State University of New Jersey, School of Health Related Professions, Newark NJ
Address correspondence to: Robert L. Dekerlegand, PT, MPT, CCS, Rutgers, The State University of New Jersey School of Health Related Professions, Doctor of Physical Therapy Program--Stratford, 40 East Laurel Road Stratford, NJ 08084 (email@example.com).
Table 1. Baseline Characteristics of the Study Population Subject A B Genotype [DELTA]F508/ [DELTA]F508/ other [DELTA]F508 Gender (M/F) F M CFRD (Y/N) N Y PI (Y/N) Y Y Age (yrs) 28 22 Height (cm) 160.0 165.1 Weight(kg) 51.4 60.5 BMI 20.1 22.2 [FEV.sub.1] (L) 3.24 3.20 [FEV.sub.1] (% pred) 104 79 FEV/FVC (%) 83 71 [FEF.sub.25-75%] (L) 3.75 2.09 [FEF.sub.25-75%] (% pred) 108 47 MIP (cm [H.sub.2]O) 93 108 MIP (%pred) 115 99 Subject C D Genotype Unknown [DELTA]F508/ other Gender (M/F) M F CFRD (Y/N) N Y PI (Y/N) Y Y Age (yrs) 22 36 Height (cm) 166.4 162.6 Weight(kg) 73.6 50.7 BMI 26.6 19.2 [FEV.sub.1] (L) 3.46 1.35 [FEV.sub.1] (% pred) 84 44 FEV/FVC (%) 69 68 [FEF.sub.25-75%] (L) 2.45 0.79 [FEF.sub.25-75%] (% pred) 55 24 MIP (cm [H.sub.2]O) 143 60 MIP (%pred) 124 76 Subject E Group (a) Genotype [DELTA]F508/ -- other Gender (M/F) M 3/2 CFRD (Y/N) N 2/3 PI (Y/N) Y 5/0 Age (yrs) 33 28.2(6.3) Height (cm) 167.6 164.3(3.1) Weight(kg) 60.5 59.3(9.3) BMI 21.5 21.9(2.9) [FEV.sub.1] (L) 0.93 2.43(1.2) [FEV.sub.1] (% pred) 23 66.8(32.7) FEV/FVC (%) 34 65.0(0.2) [FEF.sub.25-75%] (L) 0.29 1.87(1.4) [FEF.sub.25-75%] (% pred) 7 48.2(38.4) MIP (cm [H.sub.2]O) 104 101.6(29.9) MIP (%pred) 102 103.2(18.2) Abbreviations: BMI, body mass index; CFRD, cystic fibrosis related diabetes; [FEF.sub.25-75%], mid-expiratory flow rate; [FEV.sub.1], forced expiratory volume in 1s; [FEV.sub.1]/FVC, ratio of [FEV.sub.1] to forced vital capacity, MIP, maximal inspiratory pressure; %MIP, percent-predicted maximal inspiratory pressure; PI, pancreatic insufficiency (a) Group values listed as counts for categorical variables and mean (SD) for continuous variables Table 2. Individually Prescribed Inspiratory Muscle Training Protocol (a) Intensity (b) Training Compliance Completed (c) Rate (d) Subject A 50% 890 82% Subject B 54% 585 54% Subject C 41% 1140 105% Subject D 55% 895 83% Subject E 56% 1065 99% (a) All prescribed protocols were at a frequency and duration of 30 minutes per day, 6 days per week, for 6 weeks. (b) Intensity listed as the percent of the individual's baseline maximal inspiratory pressure. (c) Training completed is presented as total minutes documented in the subject's training log. (d) Compliance rate calculated as the completed training minutes divided by the prescribed training minutes. Table 3. Individual and Group Results of the Primary Outcome Variables Before and After Training (c) MIP (cm %MIP [H.sub.2]O) Subject A pre-IMT 93 115 post-IMT 118 146 %-change 27 27 Subject C pre-IMT 143 124 post-IMT 174 151 %-change 22 22 Subject D pre-IMT 60 76 post-IMT 82 104 %-change 37 37 Subject E pre-IMT 104 102 post-IMT 117 115 %-change 13 13 Group Mean pre-IMT (a) 100.0 (34.2) 104.3 (20.9) post-IMT (a) 122.8 (38.0) (b) 129.0 (23.1) (b) %-change 23 24 %[FEV.sub.1] 6MWD (m) Subject A pre-IMT 104 501.1 post-IMT 104 502.9 %-change 0 0 Subject C pre-IMT 84 587.0 post-IMT 86 562.1 %-change 2 -4 Subject D pre-IMT 44 387.1 post-IMT 55 425.8 %-change 25 10 Subject E 582.2 pre-IMT 23 527.3-10 post-IMT 23 %-change 0 Group Mean pre-IMT (a) 63.8 (36.9) 514.4 (93.5) post-IMT (a) 67.0 (35.6) 504.5 (57.8) %-change 5 -2 Abbreviations: 6MWD, distance walked during the six-minute walk test; %[FEV.sub.1], percent-predicted forced expiratory volume in 1s; MIP, maximal inspiratory pressure; %MIP, percent-predicted maximal inspiratory pressure (a) Group values reported as mean (SD). (b) Level of significance p < 0.05 for within group comparison. (c) Subject B excluded secondary to low compliance rate. Table 4. Peripheral Oxygen Saturation, Dyspnea, and Perceived Exertion Responses during the Six-minute Walk Test Sp[O.sub.2] (%) Dyspnea RPE Distance (m) Subject A Pre-IMT 97-98 0-1 0-0.5 501.1 Post IMT 96-98 0-2 0-0.5 502.9 Subject C Pre-IMT 98-95 0-2 0-2 587.0 Post IMT 97-96 0-2 0-2 562.1 Subject D Pre-IMT 96-95 0.5-3 0.5-3 387.1 Post IMT 100 -100 0-3 0-3 425.8 Subject E Pre-IMT 94-84 0-3 0-3 582.2 Post IMT 93-82 0-3 0-3 527.3 Abbreviations: Sp[O.sub.2] peripheral oxygen saturation; RPE, rating of perceived exertion; IMT, inspiratory muscle training.