Asmanet ENFUMOSA : T. Perez Respiratory Myopathy In Steroid Dependent Asthma

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màj 23/07/98

ENFUMOSA
(courriel: Chanez (at) montp.inserm.fr )
The European Network For Understanding
Mechanisms of Severe Asthma
BIOMED 2 Program - European Commission

4th quaterly meeting, with the support of INSERM and
Merck Sharp & Dhome Laboratory
February 13-14th 1998 in Montpellier- France
(see programm, abstracts and experts comments )

Respiratory Myopathy In Steroid Dependent Asthma
Thierry PEREZ
Service de Pneumologie et Immuno-Allergologie,
Hôpital Calmette, C.H.R.U de Lille. 59037 Lille Cedex

Vendredi 13 Février 1988		Présentateurs/Speakers		Modérateurs	Experts
8h30-10h00	Aspects cliniques Clincal aspects	P. Godard (Montpellier) B. Wallaert (Lille) T. Perez (Lille) Discussion	15' 15' 15' 45'	P. Duroux (Paris) C. Pison (Grenoble)	E. Bel (Leiden, NL) S. Johnston (Southampton, UK) N. Siafakas (Heraklion, G)

Oral corticosteroids are often required in the treatment of severe asthma. When used on a long term basis, they may cause many side effects including skin atrophy and peripheral myopathy. The effect of steroids on respiratory muscles has so far been mainly demonstrated in animals models with evidence of diaphragm weight loss, histochemical alterations, and a decrease in both strength and endurance after high doses of corticosteroids (1). In subjects without underlying respiratory disease the effect of a long standing corticosteroid treatment on respiratory muscle function remains controversial. Case reports of proved steroid-induced inspiratory muscle weakness have been reported (2) but prospective studies analysing inspiratory muscle strength (PImax) and endurance (IME) provided conflicting results probably due to large differences in dose and duration of therapy (3,4). In COPD and asthma the inspiratory muscle dysfunction is mainly attributed to hyperinflation and the role of corticosteroid treatment in respiratory muscle dysfunction is still debated. In fact some authors reported acute or subacute respiratory myopathy due to either intravenous or long standing high dose oral therapy (5,6) but the muscular consequences of chronic low to moderate dose of steroids in asthma remain controversial (7). Two studies demonstrated a significant correlation between the average daily dose of corticosteroids over previous months and the decrease of PImax in asthma and COPD patients (8,9). We evaluated inspiratory muscle strength and endurance in steroid dependent asthmatics in comparison with asthmatics or COPD patients exhibiting a comparable level of lung hyperinflation (10). Inspiratory muscle function was assessed by maximal inspiratory pressure (PImax) and by an incremental inspiratory threshold loading test in 19 patients with steroid dependent asthma (SDA) requiring a mean daily dose of 21 mg prednisone since 5 ± 1.4 years. They were compared to 16 healthy controls, 30 patients with chronic obstructive pulmonary disease (COPD) and 16 non steroid dependent asthmatics (NSDA). PImax as percentage of predicted values (PImax%) was not significantly different in SDA patients, NSDA patients and control subjects. A significant correlation was found between PImax and hyperinflation assessed by FRC/TLC ratio (r= 0.42; p < 0.0001). Inspiratory endurance (IME) defined as the ratio of maximal peak inspiratory pressure sustained for 2 minutes to individual PImax (Plim2/PImax) was significantly lower in SDA, NSDA and COPD groups in comparison to controls. Interestingly, IME was markedly lower in SDA patients than in COPD (p = 0.0073) and NSDA patients (p < 0.0001). Multiple regression showed that steroid dosage was the only useful variable to predict IME (r = 0.4; p = 0.01).

The finding of a significantly decreased IME in SDA patients when compared with COPD patients despite a lower level of hyperinflation in the former group allows to conclude to a deleterious effect of long term corticosteroid treatment on inspiratory muscle function in asthmatics. Clinical significance of steroid induced respiratory myopathy in patients with severe asthma remains to be determined. Impairment of inspiratory muscle strength was associated with a marked decrease of vital capacity in obese steroid dependent asthmatics (11). Inspiratory muscle weakness has also been shown to increase dyspnea and to decrease exercise performance in COPD patients (12). We studied in a population of 21 SDA patients in stable condition the relationship between functional parameters and dyspnea assessed by the Modified Dyspnea Index, which is a 12 point muldimensional score closely related to Mahler’s Baseline Dyspnea Index. The best predictors of dyspnea in this group of patients were the IME (r = 0.79; p < 0.0001) and PImax (r = 0.64; p = 0.002) , whereas dyspnea was unrelated to FEV1.

In clinical practice the increasing availability of respiratory muscle function testing in PFT laboratories should improve the recognition of steroid myopathy in the follow up of steroid dependent asthmatics. The interpretation of inspiratory muscle performance in these patients must take into account the marked confounding effect of chronic hyperinflation. Early diagnosis of steroid myopathy in patients with a deteriorating clinical status could avoid an inappropriate and detrimental increase in steroid dosage.

Therapeutic options for corticosteroid induced respiratory myopathy are at present poorly defined. Threshold inspiratory muscle training was recently shown to improve both inspiratory muscle function and symptoms in asthma patients (13). Early IMT also prevented the development of respiratory steroid myopathy in patients treated for systemic disease. At present there is no recognised drug treatment for respiratory steroid myopathy (14). Il would be of interest to evaluate in controlled studies the role of promising drugs such as clenbuterol or anabolic steroids (15 ).

In conclusion, several lines of evidence support the idea that long term steroid therapy even at moderate dose has a detectable deleterious effect on inspiratory muscle function in steroid dependent asthmatics. Longitudinal studies are needed to determine the risk factors of respiratory steroid myopathy, the long term clinical significance of such inspiratory muscle dysfunction and to evaluate its reversibility after either corticosteroid tapering or other therapeutic interventions.

Ref (1): Dejkuijzen PNR, Decramer M. - Steroid-induced myopathy and its significance to respiratory disease : a know disease rediscovered. 1992. Eur Respir J. 5: 997-1003. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Dekhuijzen PN; Decramer M
Address : Respiratory Muscle Research Unit, University Hospital, Katholieke Universiteit Leuven, Belgium.
Source : Eur Respir J, 5(8):997-1003 1992 Sep
Abstract : Skeletal muscle myopathy is a well-known side-effect of systemically administered corticosteroids. In recent years renewed attention is being paid to the involvement of the respiratory muscles and its consequent significance in pulmonary patients. Two different clinical patterns of steroid-induced muscular changes are known. In acute myopathy and atrophy after short term treatment with high doses of steroids, generalized muscle atrophy and rhabdomyolysis occur, including the respiratory muscles. Chronic steroid myopathy, occurring after prolonged treatment with moderate doses, is characterized by the gradual onset of proximal limb muscle weakness and may be accompanied by reduced respiratory muscle force. Animal studies demonstrated diaphragmatic myopathy and atrophy similar to the alterations in peripheral skeletal muscles. Fluorinated steroids induced selective type IIb (fast-twitch glycolytic) fibre atrophy, resulting in changes in contractile properties of the diaphragm. Non-fluorinated steroids may also induce histological, biochemical and functional alterations in the diaphragm. Observations in patients with collagen vascular disorders and with asthma and chronic obstructive pulmonary

Author : Janssens S; Decramer M
Address : Respiratory Division, Katholieke Universiteit, Leuven, Belgium.
Source : Chest, 95(5):1160-2 1989 May
Abstract : Two women with connective tissue disease developed a characteristic steroid-induced myopathy. Reduced maximal transrespiratory pressures indicated reduced respiratory muscle strength. Gradual steroid dosage tapering resulted in prompt clinical improvement and marked increases in respiratory muscle strength, maximal inspiratory pressure increasing by 33 percent in one patient and by 70 percent in the other. This reversible steroid-induced respiratory muscle weakness may be of great significance in reconsidering long-term steroid therapy in patients with underlying lung disease.

Ref (3): Wang Y, Zintel T, Vasquez A, Gallagher CG. - Corticosteroid therapy and respiratory muscle function in humans. 1991. Am Rev Respir Dis: 144, 108-12. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Wang YM; Zintel T; Vasquez A; Gallagher CG
Address : Department of Medicine, University of Saskatchewan, Saskatoon, Canada.
Source : Am Rev Respir Dis, 144(1):108-12 1991 Jul
Abstract : We examined the effects of prednisone administration on respiratory muscle function in humans using a double-blind study with a placebo control group. A total of 16 normal subjects were randomized to receive 20 mg prednisone daily (n = 8) or placebo daily (n = 8) for 2 wk. Inspiratory muscle strength (Pimax), expiratory muscle strength (PEmax), diaphragmatic strength (Pdimax), and inspiratory muscle endurance were measured at the beginning and end of the study. There was no significant change with treatment for Pimax (-145 +/- 7 to -138 +/- 6 cm H2O), PEmax (171 +/- 17 to 169 +/- 14 cm H2O), Pdimax (194 +/- 11 to 196 +/- 12 cm H2O), or endurance (76 +/- 3 to 77 +/- 4%) for the prednisone group and no significant difference between the two groups. We conclude that prednisone in moderate dosage has no significant effect on respiratory muscle function in humans, at least in the short term.

Author : Weiner P; Azgad Y; Weiner M
Address : Department of Medicine A, Hillel-Yaffe Medical Center, Hadera, Israel.
Source : Chest, 104(6):1788-91 1993 Dec
Abstract : Functional alterations in the inspiratory muscles were evaluated in patients receiving corticosteroids for diseases other than respiratory. Inspiratory muscle strength, as expressed by the maximal inspiratory mouth pressure (PImax), and inspiratory muscle endurance (PmPeak/PImax), using a pressure threshold breathing device, were evaluated in eight patients with normal pulmonary and inspiratory muscle functions (two patients with rapidly progressive glomerulonephritis, two with glomerulonephritis with minimal changes, two with idiopathic thrombocytopenic purpura, and two with subacute thyroiditis). There was a gradual decrease in both inspiratory muscle strength and endurance following corticosteroid administration. After 8 weeks of treatment PmPeak/PImax decreased from 84.4 +/- 2.4 to 67.9 +/- 3.1 percent (p < 0.001), while inspiratory muscle strength dropped from 126.9 +/- 9.6 to 86.5 +/- 7.4 cm H2O (p < 0.005). Gradual steroid dosage tapering resulted in marked improvement in both strength and endurance; the inspiratory muscle strength rose significantly to 112.2 +/- 8.1 cm H2O (p < 0.0005) when steroid treatment was stopped, and even more significantly 6 months later (to 123.1 +/- 8.1 cm H2O [p < 0.0001]), and the PmPeak/PImax rose to 60.6 +/- 3.4 percent (p < 0.001) and to 74.7 +/- 3.2 percent (p < 0.0001), respectively. We conclude that corticosteroids have a significant deteriorating effect on respiratory muscle function in humans....

Ref (5): Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1996; 153: 1958-1964 (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Decramer M; de Bock V; Dom R
Address : Respiratory Muscle Research Unit, Laboratory of Pneumology, Katholieke Universiteit Leuven, Belgium.
Source : Am J Respir Crit Care Med, 153(6 Pt 1):1958-64 1996 Jun
Abstract : The functional and histologic picture of steroid-induced myopathy was systematically examined in eight patients with chronic obstructive pulmonary disease (COPD) and compared with control patients with COPD matched for age, sex, and degree of airflow obstruction. Steroid-induced myopathy was associated with severe peripheral muscle weakness, quadriceps force being 23 +/- 14 versus 71 +/- 23% in control patients with COPD (p < 0.001). In addition, clear ventilatory muscle weakness was present. PImax was 37 +/- 15 versus 67 +/- 24% in control patients (p < 0.001 ), and PEmax averaged 34 +/- 10 versus 74 +/- 23% (p < 0.001). Vital capacity tended to be slightly reduced compared with that in control patients (69 +/- 21 versus 80 +/- 16%, p = 0.11). The only biochemical abnormalities associated to steroid-induced myopathy were a moderately increased lactic dehydrogenase level (697 +/- 301 versus 421 +/- 128 IU/L, p < 0.001) and an increased creatine excretion in 24-h urine (990 +/- 609 versus 159 +/- 219 mg/24 h, p< 0.001)....

Ref (6): Williams TJ, O'Hehir RE, Czarny D, Horne M, Bowes G. - Acute myopathy in severe acute asthma treated with intraveinously administred corticosteroids. Am Rev Respir Dis, 1988; 137: 460-3. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Williams TJ; O'Hehir RE; Czarny D; Horne M; Bowes G
Address : Respiratory Service, Alfred Hospital, Victoria, Australia.
Source : Am Rev Respir Dis, 137(2):460-3 1988 Feb
Abstract : An association between the use of parenteral corticosteroids in acute asthma and the development of an acute myopathy was first reported in 1977. We report 2 further cases that contribute significantly to our knowledge of this rare complication of the treatment of acute asthma. These cases demonstrate that the acute myopathy is not just a complication of the use of parenteral hydrocortisone in patients requiring ventilatory support during an episode of acute asthma. The acute myopathy can occur with several parenteral corticosteroids, may be severe (with rhabdomyolysis and myoglobinuria), and may have protracted morbidity. Prospective follow-up allowed demonstration of histopathology, electrophysiology, and also the contribution of various pharmacologic agents. Careful analysis of the evidence strongly implicates corticosteroids as the causative agent.

Ref (7): Picado C, Fiz JA, Montserrat JM, Grau JM, Fernandez-Sola J, Luengo MT, Casademont J, Agusti-Vidal A. - Respiratory and skeletal muscle function in steroid-dependent bronchial asthma. Am Rev Respir Dis, 1990; 141: 14-20. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Picado C; Fiz JA; Montserrat JM; Grau JM; Fernandez-Sola J; Luengo MT; Casademont J; Agusti-Vidal A
Address : Servei de Pneumologia, Hospital Clinic, Facultad de Medicina, Barcelona, Spain.
Source : Am Rev Respir Dis, 141(1):14-20 1990 Jan
Abstract : Respiratory and skeletal (deltoid) muscle strength were evaluated in 34 oral steroid-dependent asthmatics by use of maximal inspiratory and expiratory pressures and a myometer. The patients were compared to age- and sex-matched asthmatics who had never been on continuous oral steroid treatment. Endurance time was also studied in ten steroid-dependent asthmatics and ten controls using a pressure threshold breathing device. Nutritional status was assessed from body weight, midarm circumference, triceps skinfold (TSF), prealbumin, albumin, and total protein. An open biopsy from deltoid muscle was taken from nine steroid-dependent asthmatics and the diameter of type 1 and type 2 fibers was measured by a morphometric study. No differences were found between study and control groups either in respiratory and skeletal muscle strength or in endurance time. Steroid-dependent asthmatics showed a decrease in TSF, total protein, albumin, and potassium serum levels when compared with the control group but differences were not statistically significant after Bonferroni's adjustment for multiple comparison studies. Transversal diameter of type 2 fibers was significantly correlated with the percentage of ideal weight (r = 0.75 p less than 0.05), but not with average daily dose of steroids nor with the length of steroid treatment....

Ref (8): Decramer M, Koenrad SJ. - Corticosteroid-induced myopathy involving respiratory muscles in patients with chronic obstructive pulmonary disease or asthma. Am Rev Respir Dis, 1992; 146: 800-2. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Decramer M; Stas KJ
Address : Department of Medicine, Katholieke Universiteit Leuven, Belgium.
Source : Am Rev Respir Dis, 146(3):800-2 1992 Sep
Abstract : We made observations on two patients with asthma and one with COPD who developed steroid-induced myopathy during prolonged treatment with high doses of corticosteroids. On admission, quadriceps force was on the average reduced to 31% of predicted (range 16 to 46% of predicted, nondominant leg), and urinary excretion of creatine in 24 h averaged 687 mg (range 275 to 1,045 mg/24 hr). Respiratory muscle involvement was evidenced by reductions in PImax and PEmax, being 38% (range 36 to 39) and 48% of predicted (range 36 to 68), respectively. Tapering of treatment with corticosteroids resulted in important recovery of quadriceps force and respiratory muscle force. In all three patients, a correlation between muscle forces and steroid dose was present during reduction of the dose. After 6 months quadriceps force averaged 62% of predicted (range 31 to 85), and PImax and PEmax reached 74% (range 52 to 92) and 92% of predicted (range 80 to 106), respectively, after 3 months. Consequently, respiratory muscle force appeared to recover faster than quadriceps force. The implications of these observations for patients treated with the usual doses of corticosteroids for shorter periods require further investigation.

Ref (9): Bowyer SL, La Mothe MP, Hollister JR. - Steroid myopathy : incidence and detection in a population with asthma. J Allergy Clin Immunol, 1985; 76: 234-42. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Bowyer SL; LaMothe MP; Hollister JR
Source : J Allergy Clin Immunol, 76(2 Pt 1):234-42 1985 Aug
Abstract : Sixty steroid-treated patients with asthma were evaluated for the presence of muscle weakness by use of both manual muscle testing and the Cybex II isokinetic dynamometer. The patients were compared to age and sex-matched sedentary control subjects. Forty-eight percent of the patients (12/25) taking greater than or equal to 40 mg per day of prednisone had hip flexor strength greater than or equal to 2 SD below the mean of age and sex-matched control subjects by Cybex testing (CT). Sixty-four percent of the patients (16/25) taking greater than or equal to 40 mg per day of prednisone were found on manual muscle testing to have hip flexor weakness. Only one patient taking less than 30 mg per day of prednisone was found to have muscle weakness. Biochemical parameters, including CPK, aldolase, SGOT, LDH, and LDH isoenzymes were measured to assess the degree of steroid-induced muscle damage. They neither correlated with the degree of hip flexor:weakness as measured by CT, nor did they discriminate between patients receiving small doses and large doses of steroids. Changes in urinary excretion of creatine did not help to confirm the diagnosis of steroid myopathy. Although CT provides an objective means of assessing muscle strength in these patients, at this time no definitive chemical test is available for the diagnosis of steroid myopathy.

Ref (10): Perez T, Becquart LA, Stach B, Wallaert B, Tonnel AB. Inspiratory muscle strength and endurance in steroid dependent asthma. Am J Respir Crit Care Med, 1996; 153: 610-5 (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Perez T; Becquart LA; Stach B; Wallaert B; Tonnel AB
Address : Service de Pneumologie et Immuno-Allergologie, Hôpital Calmette, C.H.R.U., Lille, France.
Source : Am J Respir Crit Care Med, 153(2):610-5 1996 Feb
Abstract : The adverse effect of long-term steroid treatment on respiratory muscle function remains controversial. We evaluated inspiratory muscle strength and endurance in steroid-dependent asthmatics in comparison with other asthmatics or with patients with chronic obstructive pulmonary disease exhibiting a comparable level of lung hyperinflation. Inspiratory muscle function was assessed by maximal inspiratory pressure (Pimax) and by an incremental inspiratory threshold loading test in 19 patients who had had steroid-dependent asthma (SDA) requiring a mean daily dose of 20.7 +/- 0.8 mg prednisone for 5 +/- 1.4 yr. They were compared with 16 healthy control subjects, 30 patients with COPD, and 16 patients with non-steroid-dependent asthma (NSDA). Pimax as percentage of predicted values (%Pimax) was not significantly different in patients with SDA (77 +/- 5%) or NSDA (83 +/- 6%) than in control subjects (93 +/- 4%). In contrast, %Pimax was lower in patients with COPD (59 +/- 4.4%) than in those with SDA or NSDA (p < 0.05) or the control subjects (p < 0.0001). A significant correlation was found between %Pimax and hyperinflation assessed by the FRC/TLC ratio (r = 0.42; p < 0.001)....

Ref (11): Melzer E, Souhrada JF. Decrease of respiratory muscle strength and static lung volumes in obese asthmatics. Am Rev Respir Dis, 1989; 140: 1544-8 (partial abstract from http://www.healthy.net/library/search/medline.htm )

Ref (12): Wijkstra PJ, Ten Vergert EM, Van der Mark TW, Postma DS, Van Altena R, Kraan J, Koeter GH. Relation of lung function, maximal inspiratory pressure, dyspnea and quality of life with exercise capacity in patients with chronic obstructive pulmonary disease.Thorax, 1994; 49: 468-472 (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Wijkstra PJ; TenVergert EM; van der Mark TW; Postma DS; Van Altena R; Kraan J; KoÍeter GH
Address : Rehabilitation Centre, Beatrixoord Hospital, Groningen, The Netherlands.
Source : Thorax, 49(5):468-72 1994 May
Abstract : BACKGROUND--Several studies have shown that both objective and subjective measurements are related to exercise capacity in patients with chronic obstructive pulmonary disease (COPD). In this study the relative contribution of lung function, maximal inspiratory pressure, dyspnoea, and quality of life to the performance in a walking distance test and a bicycle ergometer test was investigated. METHODS--Static lung volumes, forced expiratory volume in one second (FEV1), inspiratory slow vital capacity (IVC), transfer factor for carbon monoxide (TLCO) divided by the alveolar volume (TLCO/VA), static compliance (Cst), and maximal inspiratory peak pressure (PImaxPOES) were measured in 40 patients with COPD with severe airways obstruction (mean FEV1 44% predicted, mean FEV1/IVC 37% predicted). Quality of life was assessed by the Chronic Respiratory Questionnaire (CRQ) and dyspnoea by the Borg category scale. Exercise capacity was measured by both a six minute walking distance (test) and a maximal work load of the bicycle ergometer test (Wmax). RESULTS--Spirometric values and maximal inspiratory pressure were modestly correlated with both the six minute walking test and Wmax, r values ranging from 0.50 to 0.58....

Author : Weiner P; Azgad Y; Ganam R; Weiner M
Address : Department of Medicine A, Hillel-Yaffe Medical Center, Hadera, Israel.
Source : Chest, 102(5):1357-61 1992 Nov
Abstract : In patients with asthma, the respiratory muscles have to overcome the increased resistance while they become progressively disadvantaged by hyperinflation. We hypothesized that increasing respiratory muscle strength and endurance with specific inspiratory muscle training (SIMT) would result in improvement in asthma symptoms in patients with asthma. Thirty patients with moderate to severe asthma were recruited into 2 groups; 15 patients received SIMT (group A) and 15 patients were assigned to the control group (group B) and got sham training in a double-blind group-comparative trial. The training was performed using a threshold inspiratory muscle trainer. Subjects of both groups trained five times a week, each session consisted of 1/2-h training, for six months. Inspiratory muscle strength, as expressed by the PImax at RV, increased significantly, from 84.0 +/- 4.3 to 107.0 +/- 4.8 cm H2O (p < 0.0001) and the respiratory muscle endurance, as expressed by the relationship between Pmpeak and PImax from 67.5 +/- 3.1 percent to 93.1 +/- 1.2 percent (p < 0.0001), in patients of group A, but not in patients of group B. This improvement was associated with significant improvements compared with baseline for asthma symptoms (nighttime asthma, p < 0.05; morning tightness, p < 0.05; daytime asthma, p < 0.01; cough, p < 0.005), inhaled B2 usage (p < 0.05), and the number of hospital (p < 0.05) and
sick-leave (p < 0.05) days due to asthma....

Author : Weiner P; Azgad Y; Weiner M
Address : Department of Medicine A, Hillel-Yaffe Medical Center, Hadera, Israel.
Source : Chest, 107(4):1041-4 1995 Apr
Abstract : In a previous study performed by us, functional alterations in the inspiratory muscles were evaluated in patients receiving corticosteroids for diseases other than respiratory. We have shown that patients who received high-dose steroids for several weeks developed inspiratory muscle weakness that was reversible following withdrawal of the drug treatment. The present study was designed to evaluate the ability of specific inspiratory muscle training (SIMT) to prevent the effects of a therapeutic dosage of corticosteroids on inspiratory muscle function in patients receiving the drug for diseases other than pulmonary, with no underlying respiratory or muscular disease. Twelve patients, 5 men and 7 women, with ages ranging from 19 to 41 years, who received corticosteroids for diseases other than respiratory were recruited into two groups: 6 patients were assigned to the control group and got sham training and 6 patients received SIMT while receiving corticosteroids in a single-blind group-comparative trial. In both groups, there was no difference between the post-treatment and pretreatment values as regard to the FEV1/FVC relationship....

Ref (15): Van der Heijden HFM, Dekhuijzen PNR, Folgering H, van Herwaarden CLA. Pharmacotherapy of respiratory muscles in chronic obstructive pulmonary disease. Respir Med, 1996; 90: 513-22 (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : van der Heijden HF; Dekhuijzen PN; Folgering H; van Herwaarden CL
Address : Department of Pulmonary Diseases, University Hospital Nijmegen, Netherlands.
Source : Respir Med, 90(9):513-22 1996 Oct

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