Respiratory Muscle Strength in Hyperthyroidism before and after Treatment 1, 2
NIKOLAOS M. SIAFAKAS, IRA MILONA, VASILIKI SALESIOTOU, VASILIKI FILADITAKI, NIKOLAOS TZANAKIS, and DEMOSTHENES BOUROS
Introduction
It is well known that muscle weakness is a common symptom in thyrotoxicosis (1). Skeletal muscle weakness has been shown in as many as 82070 of thyrotoxic patients, and evidence of myopathy has been found in as many as 93 0J0 by electromyography (2). Recently, it was suggested that dyspnea in hyperthyroidism may be due to weakness in the respiratory muscles (3). Previous studies reported a reduction in VC (3, 4, 6-8), in lung compliance (8), and in maximal static respiratory pressures in thyrotoxicosis (3-5,9, 10).In another study significant diaphragmatic weakness was demonstrated in one patient with hyperthyroidism (3). Respiratory muscle weakness has been reported to be reversible after treatment (3, 4). However, all these studies failed to show any relationship between the function of the thyroid gland and weakness in respiratory muscles. Wetherefore studied lung volumes and maximal static pressures in patients with thyrotoxicosis before and 3 months after medical treatment and in a matched group of normal subjects, aiming in particular to investigate respiratory muscle strength in relation to thyroid function. Methods Westudied 20 consecutivethyrotoxic patients, 10 men and 10 women, and 20 normal subjects matched for sex and age. The patients' mean age was 40.25 ± 13.4 (SD) yr, mean height was 168.3 ± 9.8 em, and mean weight was 63.7 ± 13.3 kg at the entry to the study and 65.3 ± 11.3 kg 3 months after treatment. The diagnosis of hyperthyroidism was made by clinical examination and confirmed by measuring tri-iodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH). Measurements of T3 and T4 were made by radioimmunoassay techniques (Amerlex T3 and T4; Amersham, Buckinghamshire, UK) and TSH by the sensitive IRMA-sandwich method (kit LSA-TSH by CIS [GIF-SUR-Yvette-Sedex, France)). The coefficient of variation within and between
SUMMARY We undertook this study to investigate respiratory muscle strength in relation to thyroid function in 20 thyrotoxic patients and In a group of 20 normal sUbjects matched for age and sex. Global respiratory muscle strength was assessed by measuring mouth pressure during maximal static inspiratory (Plmax) and expiratory (PEmax) efforts. We also measured ve, FVe, and FEV, as well as thyroid-related hormones (T3, T4, TSH). Measurements were made once in normal sub[eets and twice In thyrotoxic patients, before and 3 months after medical treatment. Our results showed that both maximal pressures were significantly reduced (p < 0.0001) before treatment In thyrotoxic patients In relation to the mean values of the normal subjects (p < 0.0001), and they increased significantly (p < 0.0003) after treatment. Lung volumes were significantly reduced (p < 0.0001) before and increased significantly (p < 0.008) after treatment. The ratio FEV,/FVe did not change. A statistically significant linear relationship was found when Plmax of patients with thyrotoxIcosis before treatment and of normal subjects were plotted against thyroid hormones (T3, T4) (r 0.746 and r 0.745, respectively, p < 0.001). Similarly, a statistically significant linear relationship was found between PEmax and T3 and T4 (r -0.837 and r -0.838, respectively, p < 0.001). No relationship was found between maximal pressures and TSH. Finally, a significant linear relationship was found between Plmax and PEmax (r = 0.872, P < 0.001). Our results confirm that In thyrotoxicosis respiratory muscle weakness occurs that affects both Inspiratory and expiratory muscles. Furthermore, our results demonstrated that respiratory muscle strength was proportional to the degree of thyroid dysfunction. Respiratory muscle weakness was reversible with medical treatment. AM REV RESPIR DIS 1992; 146:1025-1029
=-
=-
assays did not exceed 4.7070 at any level. The normal range for T3 was 52 to 196ng/dl, for T4 it was 6.4 to 12.5 mg/dl, and for TSH it was 0.26-3.5 I-lU/mi. Patients were not selectedaccording to specific symptoms (dyspnea) or signs (muscle weakness). However, patients with cardiac failure or severe arrythmias were excluded, as well as those receiving beta-adrenergic blockers. Six were smokers, three were exsmokers, and 11 werenonsmokers. The smokers did not change their smoking habits during the study and did not show any significant symptoms related to smoking. All measurements were made at least a month after any episodes of respiratory infection or other febrile illness. Measurements were performed at the time of diagnosis before any treatment and 3 months after the initiation of antithyroid medical treatment. Thirteen patients were treated with propylthiouracil and seven with methymazole. The normal subjects were recruited from hospital personnel, and measurements were made only once. VC, FVC, and FEV, were measured by a dry spirometer (Vitalograph, Buckingham, UK), and the ratio ofFEV,/FVC was calculated. All volumes werecorrected to BTPS and expressedas the percentageof predicted values
=
=
(11) and the ratio FEV,/FVC as a percentage ofFVC. Global respiratory muscle strength was assessed by measuring maximal static inspiratory and expiratory mouth pressures according to the method of Black and Hyatt (12). In brief, maximal static inspiratory mouth pressure (Prmax) was measured near residual volume (RV), and maximal static expiratory mouth pressure (Psmax) was measured near TLC. Subjects were seated, wore noseclips, and made efforts against an obstructed mouthpiece (cylinder) 15em long with an internal diameter of 3 em and a small leak (2 mm) at the distal end to minimize oral pres(Received in original form January 4, 1991 and in revised form January 24, 1992) 1 From the Department of Thoracic Medicine, University Hospital, University of Crete Medical School, Heraklion, Crete, and the Department of Thoracic Medicine, Evangelismos Hospital, Athens, Greece. 2 Correspondence and requests for reprints should be addressed to Professor N. M. Siafakas, M.D., Ph.D., Department of Thoracic Medicine, University Hospital, University of Crete Medical School, Heraklion, Crete, Greece.
1025
1026
SIAFAKAS, MILONA, SALESIOTOU, FILADITAKI, TZANAKIS, AND BOUROS
sure artifacts (12). A hard, stiff, rubber end connected the mouth of the subject to the instrument. The mouthpiece (cylinder)wasconnected to two pressure transducers (Maxant, Paris, France), one measuring negative pressure (range, zero to - 200 mm Hg) and the other measuring positive pressure for the expiratory pressure (range, zero to + 350 mm Hg). Both manometers had two needles, one of which rested at the highest pressure produced during the effort, which enabled us to read accurately the maximal pressure. Efforts wereconsidered satisfactory when maximal pressures weremaintained for more than 1 s. This was ensured by the examiner when both needles rested at the same point more than a second. Three efforts wererecorded, and the highest value was used for calculations. A variability of less than 5070 between the three efforts was considered acceptable. Predicted values for the maximal pressures were taken from Black and Hyatt (12). Both pressures are reported in em H 2 0 without positive or negative signs. Statistical analysis was made using Student's paired t test to evaluate statistically significant differences in the mean values between pretreatment and post-treatment data in patients. Student's t test was used to compare mean values between patients (before) and normal subjects, and the least squares method was used to calculate linear relationships. A p value less than 0.05 was considered to indicate statistical significance. Data are presented as mean ± 1 SD. Results
In the group of thyrotoxic patients the mean value (± SD) of Prmax was 75 ± 24 em H 20 before and 135 ± 35 em H 20 after 3 months 0 f treatment. In the same group Psmax was 86 ± 29 em H 2 0 before and 151 ± 66 em H 20 after treatment. These changes were statistically significant (p < 0.0003). In addition the mean values of Prmax and Psmax measured in patients before treatment were statistically significantly reduced from those in the matched group of normal subjects (p < 0.0001). The mean values (± SD) of maximal static pressures (Prmax, Psmax) in em H 2 0 and as a percentage of predicted value, the spirometric indices rvc, FVe, FEV.), the FEV./FVe ratio, and the level of thyroid hormones (T3, T4, TSH) in the group of normal subjects and in the group of thyrotoxic patients before and 3 months after medical treatment are shown in table 1. It can be seen that the mean value of T3 and T4 decreased significantly (p < 0.0001) and that of TSH increased significantly (p < 0.008) after treatment in patients. However, only 12 (60070) of the patients became euthyroid after treat-
TABLE 1 MAXIMAL PRESSURES, LUNG VOLUMES, AND THYROID HORMONES IN NORMAL SUBJECTS AND IN THYROTOXIC PATIENTS BEFORE AND AFTER TREATMENT'
Variable
Prrnax em H2O % pred PEmax em H2O % pred VC, % pred FEV" % pred FVC. % pred FEV,/FVC, % T3, ngJdl T4, mg/dl TSH,Il U/ml
Thyrotoxic Patients (n
~
20)
Normal Subjects (n = 20)
Before Treatment
p Valuet
After Treatment
p Value:j:
116 ± 24 114 ± 25
75 ± 24 72 ± 21
< 0.0001
135 ± 35 131 ± 34
< 0.0001
160 104 112 108 113 80.1 105 9.15 2.83
± 30 ± 18 ± 14.8 ± 12.1 ± 14.3 ± 9.7 ± 38 ± 1.7 ± 1.7
86 58 86.5 92.1 88.8 83.8 484.8 19.6 1.51
± 29 16 12.4 15.1 10.5 10.5 166.7 3.8 1.82
± ± ± ± ± ± ± ±
< 0.0001 < 0.0001 < 0.0001 < 0.0001 > O.l(NS} < 0.0001 < 0.0001 < 0.01
151 99 106.5 111.1 103 85.9 195.3 12 3.74
Definition of abbreviations: Plmax ~ maximal inspiratory pressure; PEmax pressure; T3, T4, and TSH = thyroid-related hormones. • Values are mean ± SO.
± 66 ± 43 ± 16.7 ± 26.5 ± 21.6 ± 13.9 ± 87.3 ± 5.14 ± 3.1
=
< 0.0003 < 0.0001 < 0.008 < 0.007 > 0.5(NS) < 0.0001 < 0.0001 < 0.008
maximal expiratory
t p = between the mean values in patients betore treatment versus those in normal subjects (t test). 1 p = between the mean values before versus after treatment in patients (paired t test).
ment. The mean value of ve, FVe, and FEV. increased significantly after treatment in the group of thyrotoxic patients, but the ratio FEV./FVe did not change (table 1). Similarly, the mean values of lung volumes in patients before treatment were significantly lower than those in the normal subjects (table 1). A plot of Prmax expressed as percent of predicted value against T3 in patients before treatment and in the normal subjects is shown in figure 1.A highly statistically significant linear relationship was found between Prmax and T3 (r = -0.746, p < 0.001), expressed by the regression equation: Prmax (% pred)
= 123 - 0.103 T3 (1)
A plot of Prmax expressed as percent of predicted value against T4 in patients before treatment and in normal subjects is shown in figure 2. A highly statistically significant linear relationship was found between Prmax and T4 (r = -0.745, p < 0.001), expressed by the equation: Prmax (070 pred)
= 149 - 3.96 T4 (2)
Similarly, a highly statistically significant linear relationship (r = 0.837, p < 0.001) was found between Psmax expressed as % of predicted value and T3 in thyrotoxic patients before treatment and in normal subjects. This relationship is shown in figure 3, and it is expressed by the equation:
180 1
150 "Cl
.'
...
120
--
90
-S
60
Q)
..........
Fig. 1. Relationship between maximal static inspiratory pressure (Plmax), expressed as percent of predicted values (% Pred), and tri-iodothyronine (T3) in thyrotoxic patients before treatment (open circles) and in normal subjects (closed circles), the matched group. y ~ 123 - 0.103x;n = 40; r = - 0.746; P < 0.001.
P..
~
:>
:
NIKOLAOS M. SIAFAKAS, IRA MILONA, VASILIKI SALESIOTOU, VASILIKI FILADITAKI, NIKOLAOS TZANAKIS, and DEMOSTHENES BOUROS
Introduction
It is well known that muscle weakness is a common symptom in thyrotoxicosis (1). Skeletal muscle weakness has been shown in as many as 82070 of thyrotoxic patients, and evidence of myopathy has been found in as many as 93 0J0 by electromyography (2). Recently, it was suggested that dyspnea in hyperthyroidism may be due to weakness in the respiratory muscles (3). Previous studies reported a reduction in VC (3, 4, 6-8), in lung compliance (8), and in maximal static respiratory pressures in thyrotoxicosis (3-5,9, 10).In another study significant diaphragmatic weakness was demonstrated in one patient with hyperthyroidism (3). Respiratory muscle weakness has been reported to be reversible after treatment (3, 4). However, all these studies failed to show any relationship between the function of the thyroid gland and weakness in respiratory muscles. Wetherefore studied lung volumes and maximal static pressures in patients with thyrotoxicosis before and 3 months after medical treatment and in a matched group of normal subjects, aiming in particular to investigate respiratory muscle strength in relation to thyroid function. Methods Westudied 20 consecutivethyrotoxic patients, 10 men and 10 women, and 20 normal subjects matched for sex and age. The patients' mean age was 40.25 ± 13.4 (SD) yr, mean height was 168.3 ± 9.8 em, and mean weight was 63.7 ± 13.3 kg at the entry to the study and 65.3 ± 11.3 kg 3 months after treatment. The diagnosis of hyperthyroidism was made by clinical examination and confirmed by measuring tri-iodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH). Measurements of T3 and T4 were made by radioimmunoassay techniques (Amerlex T3 and T4; Amersham, Buckinghamshire, UK) and TSH by the sensitive IRMA-sandwich method (kit LSA-TSH by CIS [GIF-SUR-Yvette-Sedex, France)). The coefficient of variation within and between
SUMMARY We undertook this study to investigate respiratory muscle strength in relation to thyroid function in 20 thyrotoxic patients and In a group of 20 normal sUbjects matched for age and sex. Global respiratory muscle strength was assessed by measuring mouth pressure during maximal static inspiratory (Plmax) and expiratory (PEmax) efforts. We also measured ve, FVe, and FEV, as well as thyroid-related hormones (T3, T4, TSH). Measurements were made once in normal sub[eets and twice In thyrotoxic patients, before and 3 months after medical treatment. Our results showed that both maximal pressures were significantly reduced (p < 0.0001) before treatment In thyrotoxic patients In relation to the mean values of the normal subjects (p < 0.0001), and they increased significantly (p < 0.0003) after treatment. Lung volumes were significantly reduced (p < 0.0001) before and increased significantly (p < 0.008) after treatment. The ratio FEV,/FVe did not change. A statistically significant linear relationship was found when Plmax of patients with thyrotoxIcosis before treatment and of normal subjects were plotted against thyroid hormones (T3, T4) (r 0.746 and r 0.745, respectively, p < 0.001). Similarly, a statistically significant linear relationship was found between PEmax and T3 and T4 (r -0.837 and r -0.838, respectively, p < 0.001). No relationship was found between maximal pressures and TSH. Finally, a significant linear relationship was found between Plmax and PEmax (r = 0.872, P < 0.001). Our results confirm that In thyrotoxicosis respiratory muscle weakness occurs that affects both Inspiratory and expiratory muscles. Furthermore, our results demonstrated that respiratory muscle strength was proportional to the degree of thyroid dysfunction. Respiratory muscle weakness was reversible with medical treatment. AM REV RESPIR DIS 1992; 146:1025-1029
=-
=-
assays did not exceed 4.7070 at any level. The normal range for T3 was 52 to 196ng/dl, for T4 it was 6.4 to 12.5 mg/dl, and for TSH it was 0.26-3.5 I-lU/mi. Patients were not selectedaccording to specific symptoms (dyspnea) or signs (muscle weakness). However, patients with cardiac failure or severe arrythmias were excluded, as well as those receiving beta-adrenergic blockers. Six were smokers, three were exsmokers, and 11 werenonsmokers. The smokers did not change their smoking habits during the study and did not show any significant symptoms related to smoking. All measurements were made at least a month after any episodes of respiratory infection or other febrile illness. Measurements were performed at the time of diagnosis before any treatment and 3 months after the initiation of antithyroid medical treatment. Thirteen patients were treated with propylthiouracil and seven with methymazole. The normal subjects were recruited from hospital personnel, and measurements were made only once. VC, FVC, and FEV, were measured by a dry spirometer (Vitalograph, Buckingham, UK), and the ratio ofFEV,/FVC was calculated. All volumes werecorrected to BTPS and expressedas the percentageof predicted values
=
=
(11) and the ratio FEV,/FVC as a percentage ofFVC. Global respiratory muscle strength was assessed by measuring maximal static inspiratory and expiratory mouth pressures according to the method of Black and Hyatt (12). In brief, maximal static inspiratory mouth pressure (Prmax) was measured near residual volume (RV), and maximal static expiratory mouth pressure (Psmax) was measured near TLC. Subjects were seated, wore noseclips, and made efforts against an obstructed mouthpiece (cylinder) 15em long with an internal diameter of 3 em and a small leak (2 mm) at the distal end to minimize oral pres(Received in original form January 4, 1991 and in revised form January 24, 1992) 1 From the Department of Thoracic Medicine, University Hospital, University of Crete Medical School, Heraklion, Crete, and the Department of Thoracic Medicine, Evangelismos Hospital, Athens, Greece. 2 Correspondence and requests for reprints should be addressed to Professor N. M. Siafakas, M.D., Ph.D., Department of Thoracic Medicine, University Hospital, University of Crete Medical School, Heraklion, Crete, Greece.
1025
1026
SIAFAKAS, MILONA, SALESIOTOU, FILADITAKI, TZANAKIS, AND BOUROS
sure artifacts (12). A hard, stiff, rubber end connected the mouth of the subject to the instrument. The mouthpiece (cylinder)wasconnected to two pressure transducers (Maxant, Paris, France), one measuring negative pressure (range, zero to - 200 mm Hg) and the other measuring positive pressure for the expiratory pressure (range, zero to + 350 mm Hg). Both manometers had two needles, one of which rested at the highest pressure produced during the effort, which enabled us to read accurately the maximal pressure. Efforts wereconsidered satisfactory when maximal pressures weremaintained for more than 1 s. This was ensured by the examiner when both needles rested at the same point more than a second. Three efforts wererecorded, and the highest value was used for calculations. A variability of less than 5070 between the three efforts was considered acceptable. Predicted values for the maximal pressures were taken from Black and Hyatt (12). Both pressures are reported in em H 2 0 without positive or negative signs. Statistical analysis was made using Student's paired t test to evaluate statistically significant differences in the mean values between pretreatment and post-treatment data in patients. Student's t test was used to compare mean values between patients (before) and normal subjects, and the least squares method was used to calculate linear relationships. A p value less than 0.05 was considered to indicate statistical significance. Data are presented as mean ± 1 SD. Results
In the group of thyrotoxic patients the mean value (± SD) of Prmax was 75 ± 24 em H 20 before and 135 ± 35 em H 20 after 3 months 0 f treatment. In the same group Psmax was 86 ± 29 em H 2 0 before and 151 ± 66 em H 20 after treatment. These changes were statistically significant (p < 0.0003). In addition the mean values of Prmax and Psmax measured in patients before treatment were statistically significantly reduced from those in the matched group of normal subjects (p < 0.0001). The mean values (± SD) of maximal static pressures (Prmax, Psmax) in em H 2 0 and as a percentage of predicted value, the spirometric indices rvc, FVe, FEV.), the FEV./FVe ratio, and the level of thyroid hormones (T3, T4, TSH) in the group of normal subjects and in the group of thyrotoxic patients before and 3 months after medical treatment are shown in table 1. It can be seen that the mean value of T3 and T4 decreased significantly (p < 0.0001) and that of TSH increased significantly (p < 0.008) after treatment in patients. However, only 12 (60070) of the patients became euthyroid after treat-
TABLE 1 MAXIMAL PRESSURES, LUNG VOLUMES, AND THYROID HORMONES IN NORMAL SUBJECTS AND IN THYROTOXIC PATIENTS BEFORE AND AFTER TREATMENT'
Variable
Prrnax em H2O % pred PEmax em H2O % pred VC, % pred FEV" % pred FVC. % pred FEV,/FVC, % T3, ngJdl T4, mg/dl TSH,Il U/ml
Thyrotoxic Patients (n
~
20)
Normal Subjects (n = 20)
Before Treatment
p Valuet
After Treatment
p Value:j:
116 ± 24 114 ± 25
75 ± 24 72 ± 21
< 0.0001
135 ± 35 131 ± 34
< 0.0001
160 104 112 108 113 80.1 105 9.15 2.83
± 30 ± 18 ± 14.8 ± 12.1 ± 14.3 ± 9.7 ± 38 ± 1.7 ± 1.7
86 58 86.5 92.1 88.8 83.8 484.8 19.6 1.51
± 29 16 12.4 15.1 10.5 10.5 166.7 3.8 1.82
± ± ± ± ± ± ± ±
< 0.0001 < 0.0001 < 0.0001 < 0.0001 > O.l(NS} < 0.0001 < 0.0001 < 0.01
151 99 106.5 111.1 103 85.9 195.3 12 3.74
Definition of abbreviations: Plmax ~ maximal inspiratory pressure; PEmax pressure; T3, T4, and TSH = thyroid-related hormones. • Values are mean ± SO.
± 66 ± 43 ± 16.7 ± 26.5 ± 21.6 ± 13.9 ± 87.3 ± 5.14 ± 3.1
=
< 0.0003 < 0.0001 < 0.008 < 0.007 > 0.5(NS) < 0.0001 < 0.0001 < 0.008
maximal expiratory
t p = between the mean values in patients betore treatment versus those in normal subjects (t test). 1 p = between the mean values before versus after treatment in patients (paired t test).
ment. The mean value of ve, FVe, and FEV. increased significantly after treatment in the group of thyrotoxic patients, but the ratio FEV./FVe did not change (table 1). Similarly, the mean values of lung volumes in patients before treatment were significantly lower than those in the normal subjects (table 1). A plot of Prmax expressed as percent of predicted value against T3 in patients before treatment and in the normal subjects is shown in figure 1.A highly statistically significant linear relationship was found between Prmax and T3 (r = -0.746, p < 0.001), expressed by the regression equation: Prmax (% pred)
= 123 - 0.103 T3 (1)
A plot of Prmax expressed as percent of predicted value against T4 in patients before treatment and in normal subjects is shown in figure 2. A highly statistically significant linear relationship was found between Prmax and T4 (r = -0.745, p < 0.001), expressed by the equation: Prmax (070 pred)
= 149 - 3.96 T4 (2)
Similarly, a highly statistically significant linear relationship (r = 0.837, p < 0.001) was found between Psmax expressed as % of predicted value and T3 in thyrotoxic patients before treatment and in normal subjects. This relationship is shown in figure 3, and it is expressed by the equation:
180 1
150 "Cl
.'
...
120
--
90
-S
60
Q)
..........
Fig. 1. Relationship between maximal static inspiratory pressure (Plmax), expressed as percent of predicted values (% Pred), and tri-iodothyronine (T3) in thyrotoxic patients before treatment (open circles) and in normal subjects (closed circles), the matched group. y ~ 123 - 0.103x;n = 40; r = - 0.746; P < 0.001.
P..
~
:>
:
