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Neuromuscular electrical stimulation prevents muscle function deterioration in exacerbated COPD: A pilot study
Respiratory Medicine (2012) 106, 1429e1434
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Neuromuscular electrical stimulation prevents muscle function deterioration in exacerbated COPD: A pilot study Santiago Giavedoni a, Andrew Deans a,b, Paul McCaughey b, Ellen Drost a, William MacNee a, Roberto A. Rabinovich a,* a
ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK b The Royal Infirmary of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK Received 3 February 2012; accepted 19 May 2012 Available online 20 June 2012
KEYWORDS COPD; Skeletal muscle dysfunction; Skeletal muscle wasting; Exacerbations of COPD; Pulmonary rehabilitation; NMES
Summary Purpose: COPD is a condition with systemic effects of which peripheral muscle dysfunction is a prominent contributor to exercise limitation, health related quality of life (HRQoL) impairment, and is an independent predictor of morbidity and mortality. Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD or early after severe exacerbations of COPD (SECOPD). However, muscle function further deteriorates during SECOPD before early PR programmes commence. We aimed to investigate the feasibility and efficacy of quadriceps neuromuscular electrical stimulation (NMES) applied during a SECOPD to prevent muscle function deterioration. Methods: We have conducted a pilot study in eleven COPD patients (FEV1 41.3 5.6 % pred) admitted to hospital with a SECOPD. We randomly allocated one leg to receive NMES (once a day for 14 days) with the other leg as a control (non-stimulated leg). We measured the change in quadriceps maximal voluntary contraction (DQMVC) as the main outcome. Results: Mean quadriceps muscle strength decreased in control legs (DQMVC 2.9 5.3 N, p Z ns) but increased in the stimulated legs (DQMVC 19.2 6.1 N, p < 0.01). The difference in DQMVC between groups was statistically significant (p < 0.05). The effect of NMES was P directly related to the stimulation intensity ( mA) applied throughout the 14 sessions (r Z 0.76, p < 0.01). All patients tolerated NMES without any side effects.
* Corresponding author. Tel.: þ44 (0) 131 2429198; fax: þ44 (0) 131 242 6582. E-mail address: [email protected] (R.A. Rabinovich). 0954-6111/$ - see front matter ª 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2012.05.005
1430
S. Giavedoni et al. Conclusions: NMES is a feasible and effective treatment to prevent quadriceps muscle strength derangement during severe exacerbations of COPD and may be used to compliment early postexacerbation pulmonary rehabilitation. ª 2012 Elsevier Ltd. All rights reserved.
Introduction The natural course of Chronic Obstructive Pulmonary Disease (COPD) is complicated by the development of systemic consequences of the disease.1 Skeletal muscle dysfunction, particularly of the limb muscles, is one of the most prominent and extensively studied systemic effects2,3 and a major contributor to exercise limitation,4,5 health related quality of life (HRQoL) impairment,5 health care utilization increments6 and is an independent predictor of morbidity and mortality,7 which is partly independent of the severity of the airflow limitation.8,9 Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD10 or early after severe exacerbations of COPD (SECOPD) (w30 days after a SECOPD).11 However, SECOPD further impair muscle weakness during a SECOPD before the implementation of early PR programmes,12 which contributes to further deteriorate skeletal muscle function.12 PR programmes during a SECOPD are difficult to implement due to the clinical condition of these patients, and strategies avoiding respiratory system stress are needed.13 Neuromuscular electrical stimulation (NMES) is a muscle training technique that has been used in diverse conditions, such as stroke, orthopaedic surgery, chronic heart failure and also in COPD14e16 incurring minimal stress to the respiratory system.14,17 Moreover, it is relatively inexpensive and patients can be trained to self-administer NMES constituting an ideal strategy to prevent skeletal muscle deterioration occurring during SECOPD. The aim of this pilot study was to test the efficacy and feasibility of a short NMES programme (14 consecutive days) during SECOPD with the aim to prevent exacerbation related skeletal muscle function (strength) deterioration in COPD patients admitted to the hospital. We hypothesises that NMES administered within the first 48 h after admission and for 14 consecutive days would be feasible for patients with an exacerbation of COPD and would prevent muscle function impairment secondary to a SECOPD.
Methods
predicted). All patients were on treatment with short- and long-acting bronchodilators and inhaled corticosteroids and three patients were on long term oxygen therapy (LTOT). Exclusion criteria included: 1) Need of respiratory support or admission to intensive care unit; 2) Any condition that precluded a reliable muscle strength measurement (e.g. knee arthritis); 3) Other conditions associated with myopathy; 4) Engaged in any PR program at the time of admission; 5) Any hospital admission or ECOPD within the previous 3 months. All admitted patients received standard treatment, including nebulised bronchodilators, oxygen, oral or intravenous antibiotics and a 7e14 days course of oral prednisolone (30e40 mg daily). All participants were informed of any risks and discomfort associated with the study, and written informed consent was obtained. The study was approved by the Lothian Regional Ethics Committee.
Study design Maximal isometric voluntary contraction of both quadriceps muscles (QMVC) was measured and the dominant leg was randomly allocated to treatment with NMES or no stimulation (control) for 14 consecutive days (1 session per day) starting at the hospital and continuing at home after discharge. The QMVC was assessed again 48 h after the last NMES session (Fig. 1). A NMES protocol based on previous studies was selected.14e17 NMES was administered transcutaneously to the selected leg using an electrical stimulator (ELPHA II 3000, Danmeter, DK) through two self-
Stimulation 14 days Treatment leg
Hospital Admission
Discharge
Home Base Control leg
QMVC
QMVC
Leg randomization
Study group Eleven COPD patients (5 male), were recruited within 48 h of admission to hospital due to a SECOPD. Patients had a history compatible with COPD, at least 20 pack years of smoking history and evidence of chronic airflow limitation (post bronchodilator FEV1/FVC < 0.7, FEV1 < 80%
Figure 1 Study design. Patients were recruited within 48 h of admission to the hospital with SECOPD. Muscle strength of both quadriceps was measured and NMES was commenced in one leg during 14 consecutive days, starting in hospital and continuing at home. QMVC was measured again after 14 sessions and mean difference between groups was compared.
NMES in severe COPD exacerbations adhering surface silver electrodes (Superior Silver 612SS, Uni-Patch, MN, USA) placed longitudinally on the mid aspect of the quadriceps (5 cm distal from the inguinal ligament) and vastus medialis (5 cm proximal from the patella). An asymmetrical bi-phase pulse wave, 400 ms pulse duration, 50 Hz frequency, 8/20 s on/off cycle, in 30 min sessions was used. One session per day was applied. During this session, patients were able to regulate the intensity (mA) of the stimulation according to their tolerance. Patients received their first stimulation supervised session after the randomization, within 48 h of admission, starting with the maximum tolerated voltage and were encouraged to raise the intensity during each consecutive session thereafter. Subjects were instructed on how to use the device and on electrode placement during the first 2 supervised sessions and were then supervised in one further occasion during their admission. Once discharged from hospital, patients continued to self-administer NMES until the completion of 14 sessions. In order to guarantee the compliance with the NMES programme, one extra session was supervised at home. Patients were followed up by telephone calls (on two occasions) throughout the program and extra supervised sessions at the patient’s home were added if needed. Patients were given a diary to collect information on the maximal intensity used throughout each individual NMES session. The battery power of each device was measured before and after the period of 14 days of NMES using a digital multimeter to reassure that the patient was using the device appropriately during the 14 days period of treatment.
Measurements Anthropometric measurements Body weight was measured to the nearest 0.1 kg with a digital scale and height was measured to the nearest 0.5 cm with a stadiometer. Body mass index (BMI) was calculated as the ratio of weight (in kilogrammes) to height (in metres) squared.
1431 manoeuvre with their arms crossed in front of their chest. A strain gauge (Chatillon K-MSC 500, AMETEK, FL, USA) was attached to the back of the chair. An inextensible strap placed around the subject’s ankle was firmly attached to the dynamometer ensuring an isometric measurement. Patients performed at least three sustained maximal quadriceps contractions of between 4 and 6 s duration. Maximal tension was assessed when the force elicited reached a plateau, and a difference less than 10% between manoeuvres was reached. The maximal effort was used for analysis.
Statistical analysis Results are described as mean SEM and force units in Newton (N), unless otherwise specified, QMVC percentage of predicted values were calculated.19 Unpaired T-test was used to analyze differences between groups. The level of significance for all comparisons was set at p < 0.05. Total amount of energy used throughout the program by each subject was calculated as the sum of the maximal amount P ( mA) of each day and correlated with the gain in muscle strength in the stimulated leg by Pearson’s correlation test. Data were analyzed using the statistical package program SPSS Version 17.0 (SPSS Inc, Chicago, Illinois, USA).
Results Anthropometric characteristics and pulmonary function data of study subjects are depicted in Table 1. The patients in general had severe COPD. Body composition (BMI) was preserved and quadriceps muscle strength was below the predicted values. After randomisation, seven dominant legs were allocated to the NMES group, and 4 dominant legs were allocated to the control group. There was no difference in QMVC at baseline between legs allocated to stimulation (205.9 19.7 N) or control (206.5 22.6 N). After 14 days of stimulation/control, QMVC increased by 19.2 6.1 N (8.4 2.4%), (p < 0.01) in the stimulated legs whereas there was a decrease in muscle strength of 2.9 5.3 N (2.2 2.6%), (p Z ns) in control legs. The
Lung function Post bronchodilators spirometry was measured one month after the exacerbation when the patient was clinically stable (Alpha Spirometer; Vitalograph, Buckingham, UK) according to American Thoracic Society/European Respiratory Society standards.
Muscle strength As a recognised measurement of muscle function, quadriceps muscle strength, was assessed using the maximal isometric voluntary contraction technique (QMVC) following a standardised technique.7,18 Briefly, patients were measured while seated and secured in a purpose-built chair, with hips and knees flexed at 90 . To avoid effects on the contra lateral leg, hips and chest were fixed to the chair with a strap system and patients performed the QMVC
Table 1
Patient characteristics.
Variable
nZ11
Gender (F/M) Age (years) Height (m) Weight (Kg) BMI (Kg/m2) FEV1 (%pred) FVC (%pred) FEV1/FVC (%) QMVC (N) QMVC (%pred)
6/5 72.2 1.6 61.3 23.2 41.3 76.9 40.7 215.2 65.6
3.1 0.1 4.3 1.3 5.6 4.7 4.1 21.8 3.8
BMI Z body mass index; FEV1 Z forced expiratory volume in the first second; FVC Z forced vital capacity; QMVC Z quadriceps maximal voluntary contraction.
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S. Giavedoni et al.
Discussion This pilot study shows that a short NMES programme is feasible and effective in preventing skeletal muscle function deterioration in COPD patients during SECOPD.
A
*
60
QMVC (N)
40 20 0
SECOPD further impairs skeletal muscle function in COPD patients with an impact on exercise capacity and physical activity that is related to a higher hospital re-admission risk.12 Early PR programmes are effective at improving exercise tolerance through the improvement of muscle function.11 However, skeletal muscle function deteriorates during hospitalisations before the start of these programmes. Interventions aimed at preventing skeletal muscle deterioration during a SECOPD may result in the improvement of these outcomes and facilitate the success of early PR programmes. COPD patients admitted to hospital with a SECOPD are severely limited by dyspnoea which precludes the initiation of a conventional PR programme. Thus, strategies avoiding respiratory system stress are needed. NMES increases muscle strength in COPD patients with a very low metabolic response incurring minimal stress to the respiratory system.14,17 Interestingly, in our group of patients, a short NMES programme, aimed at preventing skeletal muscle function deterioration during SECOPD, not only prevented the deterioration of muscle function, but significantly improved muscle strength in the stimulated legs in comparison with control legs. Moreover, all the patients tolerated the NMES without any adverse effects and were capable of selfadministering the treatment. NMES therefore represents a treatment to prevent muscle derangement during a SECOPD prior to a post exacerbation PR programme which may improve the success of subsequent PR.
B
60
QMVC NMES
differences in DQMVC between treatment and control was statistically significant (p < 0.05) (Fig. 2A). The changes in DQMVC of the stimulated leg as a function of DQMVC in the control leg show a clear effect in favour of NMES (Fig. 2B). The effect of NMES on muscle strength in the stimulated leg P was directly related to the amount of energy applied ( mA) throughout the 14 days treatment (r Z 0.76, p < 0.01) (Fig. 2C). There was a clear difference in the mA tolerated by the male patients in comparison with the females (Fig. 2D). Male subjects started with higher intensity levels and were able to sustain higher increments in the mA throughout the program, reaching higher total stimulation energy levels by the end of the program. There was no relationship between days in hospital and effects of NME on QMVC. In addition, except for two patients that required no visits after discharge, and one patient that was not discharged during the 14 days of duration of the protocol, all of the remaining patients received only one extra visit at home. No patient required more than one extra visit at home. There was no relationship between visit number and the NMES effect.
30
Favours NMES
0
-30 -20
Favours Control -60
-40 NMES
Control
-60
-30
0
30
60
QMVC Control
D 100
60
Max mA per session
QMVC NMES Legs
C
40
20
r=0.76 p<0.01
0
80 60 40 20 0
200
400
600
800
mA
1000
1200
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
NMES Sessions
Figure 2 (A) Individual data of DQMVC (Newton) from both NMES and control legs, horizontal line represent group means. (B) DQMVC of stimulated leg as a function of DQMVC of the control leg showing a clear favourable effect of NMES n QMVC. (C) Pearson’s P correlation coefficient between change in muscle force (DQMVC) and amount of energy ( mA) applied throughout the program to the stimulated legs (r Z 0.76, p < 0.01). (D) Mean and SEM (error bars) of maximal mA used in each NMES session by male and female patients. Male subjects are represented as black closed circles. *p < 0.05.
NMES in severe COPD exacerbations Other strategies have also been successful to prevent deterioration of skeletal muscle function during hospitalisation in COPD patients. Troosters et al.20 successfully used a bench resistance training programme during a SECOPD to train quadriceps muscles during hospital admissions (8 days). However, such a programme need to be administered in hospital20 and requires trained personnel to be provided and cannot be implemented as a self e administered strategy. Another pilot study in patients with COPD admitted to an ICU unit showed that a six weeks NMES programme starting in the ICU and continuing in an inpatient unit was successful to prevent skeletal muscle function deterioration in 9 COPD patients.15 By contrast, we have shown that, a short NMES programme aimed at preventing further muscle function deterioration in patients admitted to a general ward can produce similar effects without the need for direct supervision and can be used as a self-administered home based treatment, facilitating the implementation of early discharge programmes and may constitute a measure to compliment early postexacerbation PR. Interestingly, we found a direct relationship between the effect of the program P (gain in QMVC) and the estimated intensity of stimulation ( mA). This is not surprising and confirms previous findings showing a direct relationship between training intensity and improvement of outcomes.21e23 It is of note that patients included in the present study were encouraged to increase the intensity (mA) of the training throughout the treatment period. The intensity of the NMES stimulation depends greatly on patient tolerance and adherence to the programme. In line with previous reports,14,16 our programme was very well tolerated and the patients were able to successfully increase the training stimulation intensity (Fig. 2D). It is, thus, mandatory to reassure the adherence and compliance of the patients with the NMES programme to guarantee its effects. This was achieved by simple measurements such as telephone follow-up and a diary to collect information on the intensity achieved in each session. To guarantee the effectiveness of the programme, extra supervised sessions at the patient’s home were added if needed. The adherence and compliance with the programme was very good in this group of patients as reflected by the measurements of the battery power of each device before and after the period of 14 days of NMES. It is worthwhile mentioning, however, that we found that the rate of stimulation energy increment was lower among the female population of the study. This can be attributed to the lower electrical stimulation pain threshold previously described in female patients receiving NMES.24 In fact we found that women trained with an overall reduced energy intensity (Fig. 2D) and subjectively less muscle contraction than males. This could, to some extent, explain the difference in the NMES effect between genders.
Limitations of the study A potential caveat of the study was the absence of a sham control leg as an unbiased control, but the fact that the patients were allowed to control the intensity of stimulation (power control based on pain tolerance) together with
1433 the use of different protocols in each leg, made the implementation of sham stimulation unviable. The relatively small number of subjects constitutes a potential limitation of the study. The novelty of the study made difficult the calculation of a sample size in advance. However, significant results were found despite the relatively small population and the retrospectively calculated statistical power of the primary outcome (improvement in QMVC force) was 80%. The results of this pilot study needs to be reproduced in a larger clinical trial. The results of this pilot study constitute highly valuable information for the design of such a trial. Lastly, we have used a muscle measurement technique that depends on the subject effort. However, this voluntary contraction technique has been extensively used before and showed a good correlation with less volitional methods such us magnetic stimulation technique.25 It can be argued that the QMVC manoeuvre is biased by the fact that the patients know which leg is being stimulated. However, the high correlation between the intensity of NMES and the improvement of muscle strength in the stimulated leg together with the absolute lack of such an association in the non stimulated leg contradicts this argument.
Conclusion This pilot study shows that a short NMES programme aimed at preventing further muscle weakness development in COPD patients admitted to a general ward due to a SECOPD is feasible and effective to prevent skeletal muscle function deterioration associated with exacerbations of the disease. NMES may constitute a measure to compliment early postexacerbation PR programmes. These findings need to be reproduced in a larger clinical trial.
Conflict of interests The author declares no conflict of interests.
Acknowledgements The authors would like to thank the British Lung Foundation for their financial support (Trevor Clay, Tc07/09). Dr. SG was supported by an ERS long term research fellowship.
References 1. Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33(5):1165e85 [Epub 2009/05/02]. 2. Agusti AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 2003;21(2):347e60 [Epub 2003/03/01]. 3. Man WD, Kemp P, Moxham J, Polkey MI. Skeletal muscle dysfunction in COPD: clinical and laboratory observations. Clin Sci (Lond) 2009;117(7):251e64. 4. Saey D, Debigare R, LeBlanc P, Mador MJ, Cote CH, Jobin J, et al. Contractile leg fatigue after cycle exercise: a factor limiting exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168(4):425e30 [Epub 2003/04/26].
1434 5. Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171(9):972e7 [Epub 2005/01/25]. 6. Decramer M, Gosselink R, Troosters T, Verschueren M, Evers G. Muscle weakness is related to utilization of health care resources in COPD patients. Eur Respir J 1997;10(2):417e23 [Epub 1997/02/01]. 7. Swallow EB, Reyes D, Hopkinson NS, Man WD, Porcher R, Cetti EJ, et al. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 2007;62(2):115e20 [Epub 2006/11/09]. 8. Jones PW. Issues concerning health-related quality of life in COPD. Chest 1995;107(5 Suppl):187Se93S [Epub 1995/05/01]. 9. Seymour JM, Spruit MA, Hopkinson NS, Natanek SA, Man WD, Jackson A, et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 2010;36(1):81e8 [Epub 2009/11/10]. 10. Ries AL, Bauldoff GS, Carlin BW, Casaburi R, Emery CF, Mahler DA, et al. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based clinical practice guidelines. Chest 2007;131(5 Suppl):4Se42S. 11. Puhan M, Scharplatz M, Troosters T, Walters EH, Steurer J. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2009;1 [CD005305. Epub 2009/01/23]. 12. Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R. Physical activity and hospitalization for exacerbation of COPD. Chest 2006;129(3):536e44. 13. Man WD, Kemp P, Moxham J, Polkey MI. Exercise and muscle dysfunction in COPD: implications for pulmonary rehabilitation. Clin Sci (Lond) 2009;117(8):281e91 [Epub 2009/08/20]. 14. Sillen MJ, Janssen PP, Akkermans MA, Wouters EF, Spruit MA. The metabolic response during resistance training and neuromuscular electrical stimulation (NMES) in patients with COPD, a pilot study. Respir Med 2008;102(5):786e9 [Epub 2008/02/26]. 15. Abdellaoui A, Prefaut C, Gouzi F, Couillard A, Coisy-Quivy M, Hugon G, et al. Skeletal muscle effects of electrostimulation after COPD exacerbation: a pilot study. Eur Respir J 2011 [Epub 2011/02/26].
S. Giavedoni et al. 16. Meglic U, Sorli J, Kosnik M, Lainscak M. Feasibility of transcutaneous electrical muscle stimulation in acute exacerbation of COPD. Wien Klin Wochenschr 2011;123(11e12):384e7 [Epub 2011/05/25. Durchfuhrbarkeit einer transcutanen elektrischen Muskelstimulation bei akuter Exazerbation einer COPD]. 17. Sillen MJ, Wouters EF, Franssen FM, Meijer K, Stakenborg KH, Spruit MA. Oxygen uptake, ventilation, and symptoms during low-frequency versus high-frequency NMES in COPD: a pilot study. Lung 2011;189(1):21e6 [Epub 2010/11/17]. 18. Edwards RH, Young A, Hosking GP, Jones DA. Human skeletal muscle function: description of tests and normal values. Clin Sci Mol Med 1977;52(3):283e90. 19. Stoll T, Huber E, Seifert B, Michel BA, Stucki G. Maximal isometric muscle strength: normative values and genderspecific relation to age. Clin Rheumatology 2000;19(2): 105e13 [Epub 2000/05/03]. 20. Troosters T, Probst VS, Crul T, Pitta F, Gayan-Ramirez G, Decramer M, et al. Resistance training prevents deterioration in quadriceps muscle function during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181(10):1072e7 [Epub 2010/02/06]. 21. Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Review Respiratory Disease 1991;143(1):9e18. 22. Gimenez M, Servera E, Vergara P, Bach JR, Polu JM. Endurance training in patients with chronic obstructive pulmonary disease: a comparison of high versus moderate intensity. Arch Physical Medicine Rehabilitation 2000;81(1):102e9. 23. Vallet G, Ahmaidi S, Serres I, Fabre C, Bourgouin D, Desplan J, et al. Comparison of two training programmes in chronic airway limitation patients: standardized versus individualized protocols. Eur Respir J 1997;10(1):114e22. 24. Maffiuletti NA, Herrero AJ, Jubeau M, Impellizzeri FM, Bizzini M. Differences in electrical stimulation thresholds between men and women. Ann Neurol 2008;63(4):507e12 [Epub 2008/02/27]. 25. Polkey MI, Kyroussis D, Hamnegard CH, Mills GH, Green M, Moxham J. Quadriceps strength and fatigue assessed by magnetic stimulation of the femoral nerve in man. Muscle Nerve 1996;19(5):549e55 [Epub 1996/05/01].
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Neuromuscular electrical stimulation prevents muscle function deterioration in exacerbated COPD: A pilot study Santiago Giavedoni a, Andrew Deans a,b, Paul McCaughey b, Ellen Drost a, William MacNee a, Roberto A. Rabinovich a,* a
ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK b The Royal Infirmary of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK Received 3 February 2012; accepted 19 May 2012 Available online 20 June 2012
KEYWORDS COPD; Skeletal muscle dysfunction; Skeletal muscle wasting; Exacerbations of COPD; Pulmonary rehabilitation; NMES
Summary Purpose: COPD is a condition with systemic effects of which peripheral muscle dysfunction is a prominent contributor to exercise limitation, health related quality of life (HRQoL) impairment, and is an independent predictor of morbidity and mortality. Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD or early after severe exacerbations of COPD (SECOPD). However, muscle function further deteriorates during SECOPD before early PR programmes commence. We aimed to investigate the feasibility and efficacy of quadriceps neuromuscular electrical stimulation (NMES) applied during a SECOPD to prevent muscle function deterioration. Methods: We have conducted a pilot study in eleven COPD patients (FEV1 41.3 5.6 % pred) admitted to hospital with a SECOPD. We randomly allocated one leg to receive NMES (once a day for 14 days) with the other leg as a control (non-stimulated leg). We measured the change in quadriceps maximal voluntary contraction (DQMVC) as the main outcome. Results: Mean quadriceps muscle strength decreased in control legs (DQMVC 2.9 5.3 N, p Z ns) but increased in the stimulated legs (DQMVC 19.2 6.1 N, p < 0.01). The difference in DQMVC between groups was statistically significant (p < 0.05). The effect of NMES was P directly related to the stimulation intensity ( mA) applied throughout the 14 sessions (r Z 0.76, p < 0.01). All patients tolerated NMES without any side effects.
* Corresponding author. Tel.: þ44 (0) 131 2429198; fax: þ44 (0) 131 242 6582. E-mail address: [email protected] (R.A. Rabinovich). 0954-6111/$ - see front matter ª 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2012.05.005
1430
S. Giavedoni et al. Conclusions: NMES is a feasible and effective treatment to prevent quadriceps muscle strength derangement during severe exacerbations of COPD and may be used to compliment early postexacerbation pulmonary rehabilitation. ª 2012 Elsevier Ltd. All rights reserved.
Introduction The natural course of Chronic Obstructive Pulmonary Disease (COPD) is complicated by the development of systemic consequences of the disease.1 Skeletal muscle dysfunction, particularly of the limb muscles, is one of the most prominent and extensively studied systemic effects2,3 and a major contributor to exercise limitation,4,5 health related quality of life (HRQoL) impairment,5 health care utilization increments6 and is an independent predictor of morbidity and mortality,7 which is partly independent of the severity of the airflow limitation.8,9 Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD10 or early after severe exacerbations of COPD (SECOPD) (w30 days after a SECOPD).11 However, SECOPD further impair muscle weakness during a SECOPD before the implementation of early PR programmes,12 which contributes to further deteriorate skeletal muscle function.12 PR programmes during a SECOPD are difficult to implement due to the clinical condition of these patients, and strategies avoiding respiratory system stress are needed.13 Neuromuscular electrical stimulation (NMES) is a muscle training technique that has been used in diverse conditions, such as stroke, orthopaedic surgery, chronic heart failure and also in COPD14e16 incurring minimal stress to the respiratory system.14,17 Moreover, it is relatively inexpensive and patients can be trained to self-administer NMES constituting an ideal strategy to prevent skeletal muscle deterioration occurring during SECOPD. The aim of this pilot study was to test the efficacy and feasibility of a short NMES programme (14 consecutive days) during SECOPD with the aim to prevent exacerbation related skeletal muscle function (strength) deterioration in COPD patients admitted to the hospital. We hypothesises that NMES administered within the first 48 h after admission and for 14 consecutive days would be feasible for patients with an exacerbation of COPD and would prevent muscle function impairment secondary to a SECOPD.
Methods
predicted). All patients were on treatment with short- and long-acting bronchodilators and inhaled corticosteroids and three patients were on long term oxygen therapy (LTOT). Exclusion criteria included: 1) Need of respiratory support or admission to intensive care unit; 2) Any condition that precluded a reliable muscle strength measurement (e.g. knee arthritis); 3) Other conditions associated with myopathy; 4) Engaged in any PR program at the time of admission; 5) Any hospital admission or ECOPD within the previous 3 months. All admitted patients received standard treatment, including nebulised bronchodilators, oxygen, oral or intravenous antibiotics and a 7e14 days course of oral prednisolone (30e40 mg daily). All participants were informed of any risks and discomfort associated with the study, and written informed consent was obtained. The study was approved by the Lothian Regional Ethics Committee.
Study design Maximal isometric voluntary contraction of both quadriceps muscles (QMVC) was measured and the dominant leg was randomly allocated to treatment with NMES or no stimulation (control) for 14 consecutive days (1 session per day) starting at the hospital and continuing at home after discharge. The QMVC was assessed again 48 h after the last NMES session (Fig. 1). A NMES protocol based on previous studies was selected.14e17 NMES was administered transcutaneously to the selected leg using an electrical stimulator (ELPHA II 3000, Danmeter, DK) through two self-
Stimulation 14 days Treatment leg
Hospital Admission
Discharge
Home Base Control leg
QMVC
QMVC
Leg randomization
Study group Eleven COPD patients (5 male), were recruited within 48 h of admission to hospital due to a SECOPD. Patients had a history compatible with COPD, at least 20 pack years of smoking history and evidence of chronic airflow limitation (post bronchodilator FEV1/FVC < 0.7, FEV1 < 80%
Figure 1 Study design. Patients were recruited within 48 h of admission to the hospital with SECOPD. Muscle strength of both quadriceps was measured and NMES was commenced in one leg during 14 consecutive days, starting in hospital and continuing at home. QMVC was measured again after 14 sessions and mean difference between groups was compared.
NMES in severe COPD exacerbations adhering surface silver electrodes (Superior Silver 612SS, Uni-Patch, MN, USA) placed longitudinally on the mid aspect of the quadriceps (5 cm distal from the inguinal ligament) and vastus medialis (5 cm proximal from the patella). An asymmetrical bi-phase pulse wave, 400 ms pulse duration, 50 Hz frequency, 8/20 s on/off cycle, in 30 min sessions was used. One session per day was applied. During this session, patients were able to regulate the intensity (mA) of the stimulation according to their tolerance. Patients received their first stimulation supervised session after the randomization, within 48 h of admission, starting with the maximum tolerated voltage and were encouraged to raise the intensity during each consecutive session thereafter. Subjects were instructed on how to use the device and on electrode placement during the first 2 supervised sessions and were then supervised in one further occasion during their admission. Once discharged from hospital, patients continued to self-administer NMES until the completion of 14 sessions. In order to guarantee the compliance with the NMES programme, one extra session was supervised at home. Patients were followed up by telephone calls (on two occasions) throughout the program and extra supervised sessions at the patient’s home were added if needed. Patients were given a diary to collect information on the maximal intensity used throughout each individual NMES session. The battery power of each device was measured before and after the period of 14 days of NMES using a digital multimeter to reassure that the patient was using the device appropriately during the 14 days period of treatment.
Measurements Anthropometric measurements Body weight was measured to the nearest 0.1 kg with a digital scale and height was measured to the nearest 0.5 cm with a stadiometer. Body mass index (BMI) was calculated as the ratio of weight (in kilogrammes) to height (in metres) squared.
1431 manoeuvre with their arms crossed in front of their chest. A strain gauge (Chatillon K-MSC 500, AMETEK, FL, USA) was attached to the back of the chair. An inextensible strap placed around the subject’s ankle was firmly attached to the dynamometer ensuring an isometric measurement. Patients performed at least three sustained maximal quadriceps contractions of between 4 and 6 s duration. Maximal tension was assessed when the force elicited reached a plateau, and a difference less than 10% between manoeuvres was reached. The maximal effort was used for analysis.
Statistical analysis Results are described as mean SEM and force units in Newton (N), unless otherwise specified, QMVC percentage of predicted values were calculated.19 Unpaired T-test was used to analyze differences between groups. The level of significance for all comparisons was set at p < 0.05. Total amount of energy used throughout the program by each subject was calculated as the sum of the maximal amount P ( mA) of each day and correlated with the gain in muscle strength in the stimulated leg by Pearson’s correlation test. Data were analyzed using the statistical package program SPSS Version 17.0 (SPSS Inc, Chicago, Illinois, USA).
Results Anthropometric characteristics and pulmonary function data of study subjects are depicted in Table 1. The patients in general had severe COPD. Body composition (BMI) was preserved and quadriceps muscle strength was below the predicted values. After randomisation, seven dominant legs were allocated to the NMES group, and 4 dominant legs were allocated to the control group. There was no difference in QMVC at baseline between legs allocated to stimulation (205.9 19.7 N) or control (206.5 22.6 N). After 14 days of stimulation/control, QMVC increased by 19.2 6.1 N (8.4 2.4%), (p < 0.01) in the stimulated legs whereas there was a decrease in muscle strength of 2.9 5.3 N (2.2 2.6%), (p Z ns) in control legs. The
Lung function Post bronchodilators spirometry was measured one month after the exacerbation when the patient was clinically stable (Alpha Spirometer; Vitalograph, Buckingham, UK) according to American Thoracic Society/European Respiratory Society standards.
Muscle strength As a recognised measurement of muscle function, quadriceps muscle strength, was assessed using the maximal isometric voluntary contraction technique (QMVC) following a standardised technique.7,18 Briefly, patients were measured while seated and secured in a purpose-built chair, with hips and knees flexed at 90 . To avoid effects on the contra lateral leg, hips and chest were fixed to the chair with a strap system and patients performed the QMVC
Table 1
Patient characteristics.
Variable
nZ11
Gender (F/M) Age (years) Height (m) Weight (Kg) BMI (Kg/m2) FEV1 (%pred) FVC (%pred) FEV1/FVC (%) QMVC (N) QMVC (%pred)
6/5 72.2 1.6 61.3 23.2 41.3 76.9 40.7 215.2 65.6
3.1 0.1 4.3 1.3 5.6 4.7 4.1 21.8 3.8
BMI Z body mass index; FEV1 Z forced expiratory volume in the first second; FVC Z forced vital capacity; QMVC Z quadriceps maximal voluntary contraction.
1432
S. Giavedoni et al.
Discussion This pilot study shows that a short NMES programme is feasible and effective in preventing skeletal muscle function deterioration in COPD patients during SECOPD.
A
*
60
QMVC (N)
40 20 0
SECOPD further impairs skeletal muscle function in COPD patients with an impact on exercise capacity and physical activity that is related to a higher hospital re-admission risk.12 Early PR programmes are effective at improving exercise tolerance through the improvement of muscle function.11 However, skeletal muscle function deteriorates during hospitalisations before the start of these programmes. Interventions aimed at preventing skeletal muscle deterioration during a SECOPD may result in the improvement of these outcomes and facilitate the success of early PR programmes. COPD patients admitted to hospital with a SECOPD are severely limited by dyspnoea which precludes the initiation of a conventional PR programme. Thus, strategies avoiding respiratory system stress are needed. NMES increases muscle strength in COPD patients with a very low metabolic response incurring minimal stress to the respiratory system.14,17 Interestingly, in our group of patients, a short NMES programme, aimed at preventing skeletal muscle function deterioration during SECOPD, not only prevented the deterioration of muscle function, but significantly improved muscle strength in the stimulated legs in comparison with control legs. Moreover, all the patients tolerated the NMES without any adverse effects and were capable of selfadministering the treatment. NMES therefore represents a treatment to prevent muscle derangement during a SECOPD prior to a post exacerbation PR programme which may improve the success of subsequent PR.
B
60
QMVC NMES
differences in DQMVC between treatment and control was statistically significant (p < 0.05) (Fig. 2A). The changes in DQMVC of the stimulated leg as a function of DQMVC in the control leg show a clear effect in favour of NMES (Fig. 2B). The effect of NMES on muscle strength in the stimulated leg P was directly related to the amount of energy applied ( mA) throughout the 14 days treatment (r Z 0.76, p < 0.01) (Fig. 2C). There was a clear difference in the mA tolerated by the male patients in comparison with the females (Fig. 2D). Male subjects started with higher intensity levels and were able to sustain higher increments in the mA throughout the program, reaching higher total stimulation energy levels by the end of the program. There was no relationship between days in hospital and effects of NME on QMVC. In addition, except for two patients that required no visits after discharge, and one patient that was not discharged during the 14 days of duration of the protocol, all of the remaining patients received only one extra visit at home. No patient required more than one extra visit at home. There was no relationship between visit number and the NMES effect.
30
Favours NMES
0
-30 -20
Favours Control -60
-40 NMES
Control
-60
-30
0
30
60
QMVC Control
D 100
60
Max mA per session
QMVC NMES Legs
C
40
20
r=0.76 p<0.01
0
80 60 40 20 0
200
400
600
800
mA
1000
1200
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
NMES Sessions
Figure 2 (A) Individual data of DQMVC (Newton) from both NMES and control legs, horizontal line represent group means. (B) DQMVC of stimulated leg as a function of DQMVC of the control leg showing a clear favourable effect of NMES n QMVC. (C) Pearson’s P correlation coefficient between change in muscle force (DQMVC) and amount of energy ( mA) applied throughout the program to the stimulated legs (r Z 0.76, p < 0.01). (D) Mean and SEM (error bars) of maximal mA used in each NMES session by male and female patients. Male subjects are represented as black closed circles. *p < 0.05.
NMES in severe COPD exacerbations Other strategies have also been successful to prevent deterioration of skeletal muscle function during hospitalisation in COPD patients. Troosters et al.20 successfully used a bench resistance training programme during a SECOPD to train quadriceps muscles during hospital admissions (8 days). However, such a programme need to be administered in hospital20 and requires trained personnel to be provided and cannot be implemented as a self e administered strategy. Another pilot study in patients with COPD admitted to an ICU unit showed that a six weeks NMES programme starting in the ICU and continuing in an inpatient unit was successful to prevent skeletal muscle function deterioration in 9 COPD patients.15 By contrast, we have shown that, a short NMES programme aimed at preventing further muscle function deterioration in patients admitted to a general ward can produce similar effects without the need for direct supervision and can be used as a self-administered home based treatment, facilitating the implementation of early discharge programmes and may constitute a measure to compliment early postexacerbation PR. Interestingly, we found a direct relationship between the effect of the program P (gain in QMVC) and the estimated intensity of stimulation ( mA). This is not surprising and confirms previous findings showing a direct relationship between training intensity and improvement of outcomes.21e23 It is of note that patients included in the present study were encouraged to increase the intensity (mA) of the training throughout the treatment period. The intensity of the NMES stimulation depends greatly on patient tolerance and adherence to the programme. In line with previous reports,14,16 our programme was very well tolerated and the patients were able to successfully increase the training stimulation intensity (Fig. 2D). It is, thus, mandatory to reassure the adherence and compliance of the patients with the NMES programme to guarantee its effects. This was achieved by simple measurements such as telephone follow-up and a diary to collect information on the intensity achieved in each session. To guarantee the effectiveness of the programme, extra supervised sessions at the patient’s home were added if needed. The adherence and compliance with the programme was very good in this group of patients as reflected by the measurements of the battery power of each device before and after the period of 14 days of NMES. It is worthwhile mentioning, however, that we found that the rate of stimulation energy increment was lower among the female population of the study. This can be attributed to the lower electrical stimulation pain threshold previously described in female patients receiving NMES.24 In fact we found that women trained with an overall reduced energy intensity (Fig. 2D) and subjectively less muscle contraction than males. This could, to some extent, explain the difference in the NMES effect between genders.
Limitations of the study A potential caveat of the study was the absence of a sham control leg as an unbiased control, but the fact that the patients were allowed to control the intensity of stimulation (power control based on pain tolerance) together with
1433 the use of different protocols in each leg, made the implementation of sham stimulation unviable. The relatively small number of subjects constitutes a potential limitation of the study. The novelty of the study made difficult the calculation of a sample size in advance. However, significant results were found despite the relatively small population and the retrospectively calculated statistical power of the primary outcome (improvement in QMVC force) was 80%. The results of this pilot study needs to be reproduced in a larger clinical trial. The results of this pilot study constitute highly valuable information for the design of such a trial. Lastly, we have used a muscle measurement technique that depends on the subject effort. However, this voluntary contraction technique has been extensively used before and showed a good correlation with less volitional methods such us magnetic stimulation technique.25 It can be argued that the QMVC manoeuvre is biased by the fact that the patients know which leg is being stimulated. However, the high correlation between the intensity of NMES and the improvement of muscle strength in the stimulated leg together with the absolute lack of such an association in the non stimulated leg contradicts this argument.
Conclusion This pilot study shows that a short NMES programme aimed at preventing further muscle weakness development in COPD patients admitted to a general ward due to a SECOPD is feasible and effective to prevent skeletal muscle function deterioration associated with exacerbations of the disease. NMES may constitute a measure to compliment early postexacerbation PR programmes. These findings need to be reproduced in a larger clinical trial.
Conflict of interests The author declares no conflict of interests.
Acknowledgements The authors would like to thank the British Lung Foundation for their financial support (Trevor Clay, Tc07/09). Dr. SG was supported by an ERS long term research fellowship.
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