© 1(>9I S. Karger AG. Basel 0025-7931 /9 1/0582-0029 S 2.75/0
Respiration 1991;58:29-32
Effect of Digoxin on Respiratory Muscle Performance in Patients with COPD D. Liberman, J.L. Bratni, H. Bark, D. Pilpel, D. Heimer Departments of Pulmonary Diseases and Internal Medicine, Soroka Medical Center, Faculty for Health Sciences, Ben Gurion University of the Negev, and School of Veterinary Medicine, Hebrew University of Jerusalem, Israel
Key Words. Maximal inspiratory pressure • Maximal expiratory pressure ■Digoxin • Chronic obstructive lung disease Abstract. The effect of 2 weeks oral digoxin administration on respiratory muscle performance (RMP) in 14 patients with chronic obstructive lung disease (COPD) was investigated in a randomized double-blind placebo-controlled cross-over study. All patients were ambulatory with severe air flow obstruction. FEVi/FVC was 0.44±(SD)0.11, FEV| was 0.88±(SD)0.35 liter/s RMP was assessed by measuring maximal inspiratory pressure (Pimax), maximal expiratory pressure (PEmax), and maximal voluntary ventilation. Although these parameters were significantly reduced in the COPD patients, 2 weeks of digoxin administration (with serum levels in the therapeutic range) did not alter any parameter of RMP or spirometry. We conclude that digoxin has no effect on RMPor spirometry in ambulatory patients with severe COPD.
Digitalis has been shown to have a positive in otropic effect on the myocardium [1,2]. Its effects on limb skeletal and respiratory muscles are question able, as various studies have produced differing re sults [3, 15, 16]. The diaphragm is the main muscle of inspiration and histologically, it resembles skeletal muscle. However, functionally and physiologically it behaves more like the myocardium [4]. It is chroni cally active and is the only skeletal muscle that can be considered as a vital organ. In addition, like the myo cardium, the diaphragm utilizes extracellular calcium for contraction. Previous studies showed that digoxin improved diaphragm contractility in anesthetized dogs [5] and in patients with chronic obstructive pul monary disease (COPD) in respiratory failure during mechanical ventilation [6]. Recent studies on isolated rat and piglet hemidiaphragms failed to demonstrate any change in contractility due to digoxin [7, 8]. To date, no clinical study has investigated the effect of digoxin on respiratory muscle performance (RMP)
in ambulatory COPD patients. COPD patients are known to have respiratory muscle dysfunction caused by several different factors. The present study was designed to evaluate the effect of digoxin on RMP of patients with severe air flow obstruction. Methods Patients 14 male patients recruited from the pulmonary clinic Soroka Medical Center, mean age of 61 years (range 44-78) with chronic obstructive pulmonary disease (emphysema an d /o r chronic bron chitis) were the subjects of this study. All patients were exsmo kers with severe air flow obstruction (mean FEV,: 0.88±SD)0.35 liter/s FVC 2.0±SD0,59 liters and FEV/VC 0.44 + SD 0.10). All patients were clinically in stable condition without any evidence of congestive heart failure, based on radiography and physical examination. They were all receiving [T-agonists and slow-release theophylline. None of them received supplemental oxygen. All medications were continued during the study period. The results of the blood chemistries (SMA-12) were within normal limits in all patients. Written informed consent, approved by the local human experimentation committee was obtained from all partici pants.
Downloaded by: Kings's College London 137.73.144.138 - 10/30/2017 2:05:57 AM
Introduction
30
Liberman/Brami/Bark/Pilpel/Heimer
Table 1. Data, mean (SD), for respiratory muscle performance, spirometry, dyspnea and well-being, before treatment, after placebo and after digoxin in 14 CO PD patients
Age, years PW
Cm H 2 °
PEomx, cm H20 M W , l/m in FVC, 1 FEV„1 FEV,/VC P 0 2, mm Hg Pco2, mm Hg Dyspnea Well-being
Baseline
Placebo
X
SD
X
60 57.1 139.6 38.5 2.01 0.88 0.44 71.2 41.0 2.0 2.0
10.1 15.1 43.4 15.6 0.59 0.35 0.11 6.4 4.6
56.6 139.1 37.5 1.98 0.86 0.44 74.1 41.9 2.0 1.8
SD
15.2 42.1 14.2 0.59 0.31 0.1 5.9 5.4 0.7 0.7
Digoxin X
56.1 139.9 34.9 2.0 0.85 0.43 72.9 42.1 2.2 2.2
P
SD
14.4 41.9 11.5 0.6 0.29 0.11 5.1 4.2 0.8 0.7
NS NS NS NS NS NS NS NS NS NS
Study Design The study was a randomized, double-blind, placebo-controlled cross-over trial of 4 weeks duration. Patients were assessed on entry to the study (baseline), 2 weeks later, after the placebo or digoxin and again after another 2 weeks after the cross-over. There was no washout period between the two parts. The initial assessment in cluded: chest X-ray, ECG, physical examination, spirometry and arterial blood gas (ABG) determinations. RMP was measured by maximal static inspiratory pressure (P|m„), maximal static expira tory pressure (PEmax). and maximal voluntary ventilation (M W ). At the end of each of the two assessment periods, serum levels for digoxin and theophylline were obtained. After baseline assessment, the patients were randomly assigned to oral digoxin (0.5 mg for the first 2 days and then 0.25 mg for the next 12 days) or placebo (the same number of tablets). Two weeks later, the alternate therapy was given. Compliance was assessed by serum digoxin levels and tablet counting. At the end of each period, the patients answered a ques tionnaire about their subjective feelings regarding their dyspnea and general well-being. At baseline assessment, those variables were given a score of 2. At the next two assessments they were given a score of I if the patient reported worsening of his condition, and a score of 3 if the patient reported an improvement in his condition. Respiratory Muscle Performance and Pulmonary Function Testing Spirometry was done by Vitalograph compact. M W was tested by using a 12-second M W test. RMP was examined by measuring Pim>, at residual volume and PEmax at total lung capacity against an obstructed airway with a small air leak to minimize the oral pres sure artifact. The apparatus used was similar to that described by Black and Hyatt [9] and was modified in the following manner: the diaphragm gauges were replaced with a Setra System pressure transducer Model 239e which was connected to a storage oscillo scope, a constellation that enabled visual feedback of the pressure signal to the patients. Every subject performed 3-6 maximal inspi ratory and expiratory efforts through a tubed mouthpiece, each lasting at least 1 s. The subjects were in seated position, wearing
Statistical Analysis Statistical analysis was done by comparison between the 3 dif ferent stages through the comparison of means of the different con tinuous variables, using one-way analysis of variance. For the dyspnea and well-being, which are discrete variables, the Freed man test was used. Results are expressed as means ± SD.
Results The mean ± SD results of the different variables for the 3 phases of the study are presented in table 1. Pimax and PEmax were both significantly reduced (p M W or spirometry (table 1). Possible explanations for the differences in response to digoxin may lie in the high dose levels used in ani mal experiments as compared to the therapeutic levels used in the clinical experiments. Alternatively, a spe cies difference may exist as postulated by others. The diaphragm is considered a unique muscle in that histologically it resembles skeletal muscle but functionally and physiologically it behaves more like the myocardium as it is chronically active and it uti lizes extracellular calcium for contraction like the my ocardium. Our study has shown that it does not re spond to digoxin as does the myocardium. We do not believe that theophylline or the (i2-agonists may have markedly affected the respiratory muscle response to digoxin, as they were being administered for long periods before the dogixin studies were started. For our study we chose to use a noninvasive tech nique for the assessment of RMP by measuring Pimax, PEmaX ar,d M W under the assumption that P|max is
32
13 Aubier, M.; De Troyer, A.; Sampson, M.; Macklem, P.T.; Roussos, C : Aminophylline improves diaphragmatic contractility. New Engl. J. Med. 305: 249-252(1981). 14 Aubier, M.; Viires, N.; Murciano, D.; et al.: Effect and mecha nism of action of terbutalin on diaphragmatic contractility and fatigue. J. appl. Physiol. 56: 922-929(1984). 15 D’Alonzo, A.; Argentieri, T.; Mcardle, J.: Ouabain and tetrodotoxin block the myotonia of skeletal muscle induced with 20,25-diazacholesterol. J. Pharmacol, exp. Ther. 222; 401-404 (1982). 16 Fujino, S.; Fujino, M.: Ouabain potentiation and Ca release from sarcoplasmic reticulum in cardiac and skeletal muscle cells. Can. J. Physiol. Pharmacol. 60: 542-555(1982). 17 Kikuchi, Y.; Hida, W.; Shindoh, C.; Chonan, C.; Miki, H.; Sakurai, M.; Inour, H.; Takishima, T.: Effect of digoxin on the diaphragm in anesthetized dogs. J. appl. Physiol. 63: 277-284 (1987).
Received: December 19, 1989 Accepted after revision: November 21,1990 Dr. D. Heimer Pulmonary Unit Soroka Medical Center PO Box 151 Beersheva (Israel)
Downloaded by: Kings's College London 137.73.144.138 - 10/30/2017 2:05:57 AM
4 Aubier. M.; Viires, N.: Piquet, J.: Murciano, D.; Blanchet, F.: Marty, C.; Gherardi, R.; Pariente, R.: Effect of hypocalcemia on diaphragmatic strength generation. J. appl. Physiol. 58: 2054-2061 (1985). 5 Aubier, M.; Viires, N.: Murciano, D.; et al.: Effect of digoxin on diaphragmatic strength generation. J. appl. Physiol. 61: 1767-1774(1986). 6 Aubier, M.; Murciano, D.: Viires, N.; et al.: Effect of digoxin on diaphragmatic strength generation in patients with chronic ob structive pulmonary disease during acute respiratory failure. Am. Rev. resp. Dis. 135: 544-548(1987). 7 Mayock, D.: Standaert, T.; Woodrum, D.: Effect of digoxin on diaphragmatic contractility in piglet. Pediatr. Res. 25: 271 -273 (1989). 8 Sherman, M.: Aldrich, T.; Chaudhry, I.; Nagashima, H.: The effect of digoxin on contractility and fatigue of isolated guinea pig and rat hemidiaphragm. Am. Rev. resp. Dis. 138: I ISO1184 (1988). 9 Black, L.E.; Hyatt, R.E.: Maximal respiratory pressure-normal values and relationship to age and sex. Am. Rev. resp. Dis. 99: 696-702(1969). 10 Rochester, D.: Arora, N.: Respiratory muscle failure. Med. Clin. N. Am. 67; 573-597 (1983). 11 Mathur, P.: Powles, A.; Pugsley, S.; et al.: Effect of long-term administration of digoxin on exercise performance in chronic airflow obstruction. Eur. J. resp. Dis. 66: 273-283 (1985). 12 Brown, S.E.; Pakron, F.J.; Milne, N.; et al.: Effects of digoxin on exercise capacity and right ventricular function during exer cise in chronic airflow obstruction. Chest 85: 187-191(1984).
Liberman/Bram ¡/Bark/Pilpel/Heimer
Respiration 1991;58:29-32
Effect of Digoxin on Respiratory Muscle Performance in Patients with COPD D. Liberman, J.L. Bratni, H. Bark, D. Pilpel, D. Heimer Departments of Pulmonary Diseases and Internal Medicine, Soroka Medical Center, Faculty for Health Sciences, Ben Gurion University of the Negev, and School of Veterinary Medicine, Hebrew University of Jerusalem, Israel
Key Words. Maximal inspiratory pressure • Maximal expiratory pressure ■Digoxin • Chronic obstructive lung disease Abstract. The effect of 2 weeks oral digoxin administration on respiratory muscle performance (RMP) in 14 patients with chronic obstructive lung disease (COPD) was investigated in a randomized double-blind placebo-controlled cross-over study. All patients were ambulatory with severe air flow obstruction. FEVi/FVC was 0.44±(SD)0.11, FEV| was 0.88±(SD)0.35 liter/s RMP was assessed by measuring maximal inspiratory pressure (Pimax), maximal expiratory pressure (PEmax), and maximal voluntary ventilation. Although these parameters were significantly reduced in the COPD patients, 2 weeks of digoxin administration (with serum levels in the therapeutic range) did not alter any parameter of RMP or spirometry. We conclude that digoxin has no effect on RMPor spirometry in ambulatory patients with severe COPD.
Digitalis has been shown to have a positive in otropic effect on the myocardium [1,2]. Its effects on limb skeletal and respiratory muscles are question able, as various studies have produced differing re sults [3, 15, 16]. The diaphragm is the main muscle of inspiration and histologically, it resembles skeletal muscle. However, functionally and physiologically it behaves more like the myocardium [4]. It is chroni cally active and is the only skeletal muscle that can be considered as a vital organ. In addition, like the myo cardium, the diaphragm utilizes extracellular calcium for contraction. Previous studies showed that digoxin improved diaphragm contractility in anesthetized dogs [5] and in patients with chronic obstructive pul monary disease (COPD) in respiratory failure during mechanical ventilation [6]. Recent studies on isolated rat and piglet hemidiaphragms failed to demonstrate any change in contractility due to digoxin [7, 8]. To date, no clinical study has investigated the effect of digoxin on respiratory muscle performance (RMP)
in ambulatory COPD patients. COPD patients are known to have respiratory muscle dysfunction caused by several different factors. The present study was designed to evaluate the effect of digoxin on RMP of patients with severe air flow obstruction. Methods Patients 14 male patients recruited from the pulmonary clinic Soroka Medical Center, mean age of 61 years (range 44-78) with chronic obstructive pulmonary disease (emphysema an d /o r chronic bron chitis) were the subjects of this study. All patients were exsmo kers with severe air flow obstruction (mean FEV,: 0.88±SD)0.35 liter/s FVC 2.0±SD0,59 liters and FEV/VC 0.44 + SD 0.10). All patients were clinically in stable condition without any evidence of congestive heart failure, based on radiography and physical examination. They were all receiving [T-agonists and slow-release theophylline. None of them received supplemental oxygen. All medications were continued during the study period. The results of the blood chemistries (SMA-12) were within normal limits in all patients. Written informed consent, approved by the local human experimentation committee was obtained from all partici pants.
Downloaded by: Kings's College London 137.73.144.138 - 10/30/2017 2:05:57 AM
Introduction
30
Liberman/Brami/Bark/Pilpel/Heimer
Table 1. Data, mean (SD), for respiratory muscle performance, spirometry, dyspnea and well-being, before treatment, after placebo and after digoxin in 14 CO PD patients
Age, years PW
Cm H 2 °
PEomx, cm H20 M W , l/m in FVC, 1 FEV„1 FEV,/VC P 0 2, mm Hg Pco2, mm Hg Dyspnea Well-being
Baseline
Placebo
X
SD
X
60 57.1 139.6 38.5 2.01 0.88 0.44 71.2 41.0 2.0 2.0
10.1 15.1 43.4 15.6 0.59 0.35 0.11 6.4 4.6
56.6 139.1 37.5 1.98 0.86 0.44 74.1 41.9 2.0 1.8
SD
15.2 42.1 14.2 0.59 0.31 0.1 5.9 5.4 0.7 0.7
Digoxin X
56.1 139.9 34.9 2.0 0.85 0.43 72.9 42.1 2.2 2.2
P
SD
14.4 41.9 11.5 0.6 0.29 0.11 5.1 4.2 0.8 0.7
NS NS NS NS NS NS NS NS NS NS
Study Design The study was a randomized, double-blind, placebo-controlled cross-over trial of 4 weeks duration. Patients were assessed on entry to the study (baseline), 2 weeks later, after the placebo or digoxin and again after another 2 weeks after the cross-over. There was no washout period between the two parts. The initial assessment in cluded: chest X-ray, ECG, physical examination, spirometry and arterial blood gas (ABG) determinations. RMP was measured by maximal static inspiratory pressure (P|m„), maximal static expira tory pressure (PEmax). and maximal voluntary ventilation (M W ). At the end of each of the two assessment periods, serum levels for digoxin and theophylline were obtained. After baseline assessment, the patients were randomly assigned to oral digoxin (0.5 mg for the first 2 days and then 0.25 mg for the next 12 days) or placebo (the same number of tablets). Two weeks later, the alternate therapy was given. Compliance was assessed by serum digoxin levels and tablet counting. At the end of each period, the patients answered a ques tionnaire about their subjective feelings regarding their dyspnea and general well-being. At baseline assessment, those variables were given a score of 2. At the next two assessments they were given a score of I if the patient reported worsening of his condition, and a score of 3 if the patient reported an improvement in his condition. Respiratory Muscle Performance and Pulmonary Function Testing Spirometry was done by Vitalograph compact. M W was tested by using a 12-second M W test. RMP was examined by measuring Pim>, at residual volume and PEmax at total lung capacity against an obstructed airway with a small air leak to minimize the oral pres sure artifact. The apparatus used was similar to that described by Black and Hyatt [9] and was modified in the following manner: the diaphragm gauges were replaced with a Setra System pressure transducer Model 239e which was connected to a storage oscillo scope, a constellation that enabled visual feedback of the pressure signal to the patients. Every subject performed 3-6 maximal inspi ratory and expiratory efforts through a tubed mouthpiece, each lasting at least 1 s. The subjects were in seated position, wearing
Statistical Analysis Statistical analysis was done by comparison between the 3 dif ferent stages through the comparison of means of the different con tinuous variables, using one-way analysis of variance. For the dyspnea and well-being, which are discrete variables, the Freed man test was used. Results are expressed as means ± SD.
Results The mean ± SD results of the different variables for the 3 phases of the study are presented in table 1. Pimax and PEmax were both significantly reduced (p M W or spirometry (table 1). Possible explanations for the differences in response to digoxin may lie in the high dose levels used in ani mal experiments as compared to the therapeutic levels used in the clinical experiments. Alternatively, a spe cies difference may exist as postulated by others. The diaphragm is considered a unique muscle in that histologically it resembles skeletal muscle but functionally and physiologically it behaves more like the myocardium as it is chronically active and it uti lizes extracellular calcium for contraction like the my ocardium. Our study has shown that it does not re spond to digoxin as does the myocardium. We do not believe that theophylline or the (i2-agonists may have markedly affected the respiratory muscle response to digoxin, as they were being administered for long periods before the dogixin studies were started. For our study we chose to use a noninvasive tech nique for the assessment of RMP by measuring Pimax, PEmaX ar,d M W under the assumption that P|max is
32
13 Aubier, M.; De Troyer, A.; Sampson, M.; Macklem, P.T.; Roussos, C : Aminophylline improves diaphragmatic contractility. New Engl. J. Med. 305: 249-252(1981). 14 Aubier, M.; Viires, N.; Murciano, D.; et al.: Effect and mecha nism of action of terbutalin on diaphragmatic contractility and fatigue. J. appl. Physiol. 56: 922-929(1984). 15 D’Alonzo, A.; Argentieri, T.; Mcardle, J.: Ouabain and tetrodotoxin block the myotonia of skeletal muscle induced with 20,25-diazacholesterol. J. Pharmacol, exp. Ther. 222; 401-404 (1982). 16 Fujino, S.; Fujino, M.: Ouabain potentiation and Ca release from sarcoplasmic reticulum in cardiac and skeletal muscle cells. Can. J. Physiol. Pharmacol. 60: 542-555(1982). 17 Kikuchi, Y.; Hida, W.; Shindoh, C.; Chonan, C.; Miki, H.; Sakurai, M.; Inour, H.; Takishima, T.: Effect of digoxin on the diaphragm in anesthetized dogs. J. appl. Physiol. 63: 277-284 (1987).
Received: December 19, 1989 Accepted after revision: November 21,1990 Dr. D. Heimer Pulmonary Unit Soroka Medical Center PO Box 151 Beersheva (Israel)
Downloaded by: Kings's College London 137.73.144.138 - 10/30/2017 2:05:57 AM
4 Aubier. M.; Viires, N.: Piquet, J.: Murciano, D.; Blanchet, F.: Marty, C.; Gherardi, R.; Pariente, R.: Effect of hypocalcemia on diaphragmatic strength generation. J. appl. Physiol. 58: 2054-2061 (1985). 5 Aubier, M.; Viires, N.: Murciano, D.; et al.: Effect of digoxin on diaphragmatic strength generation. J. appl. Physiol. 61: 1767-1774(1986). 6 Aubier, M.; Murciano, D.: Viires, N.; et al.: Effect of digoxin on diaphragmatic strength generation in patients with chronic ob structive pulmonary disease during acute respiratory failure. Am. Rev. resp. Dis. 135: 544-548(1987). 7 Mayock, D.: Standaert, T.; Woodrum, D.: Effect of digoxin on diaphragmatic contractility in piglet. Pediatr. Res. 25: 271 -273 (1989). 8 Sherman, M.: Aldrich, T.; Chaudhry, I.; Nagashima, H.: The effect of digoxin on contractility and fatigue of isolated guinea pig and rat hemidiaphragm. Am. Rev. resp. Dis. 138: I ISO1184 (1988). 9 Black, L.E.; Hyatt, R.E.: Maximal respiratory pressure-normal values and relationship to age and sex. Am. Rev. resp. Dis. 99: 696-702(1969). 10 Rochester, D.: Arora, N.: Respiratory muscle failure. Med. Clin. N. Am. 67; 573-597 (1983). 11 Mathur, P.: Powles, A.; Pugsley, S.; et al.: Effect of long-term administration of digoxin on exercise performance in chronic airflow obstruction. Eur. J. resp. Dis. 66: 273-283 (1985). 12 Brown, S.E.; Pakron, F.J.; Milne, N.; et al.: Effects of digoxin on exercise capacity and right ventricular function during exer cise in chronic airflow obstruction. Chest 85: 187-191(1984).
Liberman/Bram ¡/Bark/Pilpel/Heimer
