Intrinsic PEEP and Arterial Pco in Stable Patients with Chronic Obstructive Pulmonary Disease 1 - 3 2
JANUSZ HAWSZKA,4 DANIEL A. CHARTRAND, ALEJANDRO E. GRASSINO, and JOSEPH MILlC-EMILI
Introduction
Dynamic pulmonary hyperinflation and intrinsic PEEP (PEEPi) are common in critically ill patients with chronic obstructive pulmonary disease(COPD) and have profound consequences on the energetics of breathing (1-5). In the present study, we assessed the prevalence and magnitude of PEEPi in 96 stable COPD patients with varying degrees of airway obstruction. In addition, we assessed whether PEEPi plays a role in the genesis of chronic hypercapnic ventilatory failure in COPD patients.
SUMMARY Dynamic pulmonary hyperinflation and intrinsic PEEP (PEEPi) are known to play an important role in causing acute respiratory failure in COPO patients. In the present stUdy, we have explored (1) the prevalence and magnitude of PEEPi in stable COPD patients, and (2) the correlation of PEEPi with respiratory mechanics and Paco,. In 96 stable COPD patients with varying degrees of airway obstruction, we measured pulmonary flow resistance (Rq, dynamic lung compliance (CLdyn), breathing pattern, arterial blood gases, and dynamic PEEPi. Dynamic PEEPi was determined as a negative deflection in esophageal pressure from the start of inspiratory effort to the onset of inspiratory flow. A significant correlation was found between dynamic PEEPi and FEV; -0.56, P < 0.001), between PEEPi and RL (r 0.69, P < 0.001), and between Paco2 (%predicted; r and PEEPi (r 0.6, P < 0.001). These results Indicate that increased severity of airway obstruction promotes PEEPi and concomitant dynamic hyperinflation. This implies increased inspiratory work in the face of decreased effectiveness of the inspiratory muscles as pressure generators. The present results suggest that dynamic hyperinflation may play a role in causing chronic hypoventllatlon in COPD patients. AM REV RESPIR DIS 1990; 141:1194-1197
=
=
=
Methods In this retrospective study, we used the routine lung function data and records of 96 COPD patients (18women) from the archives of the Notre Dame Hospital, Montreal. Diagnosis of their disease was based on medical history and clinical examination. Their average (±SD) age, height, and weight were 60 ± 10.8 yr, 166 ± 7.8 em, and 67 ± 15.6 kg. All measurements were made in the seated position. Airflow (V) was measured with a Fleisch No. 2 pneumotachograph (Fleisch, Lausanne, Switzerland) connected to a differential pressure transducer (Sanborn, model 270, Waltham, MA). Changes in lung volume were obtained by electronic integration of the flow signal (Hewlett-Packard, 8815A, Waltham, MA). The deadspace of the circuit was 70 ml and the equipment resistance 1.1 cm H 20/L/s. Pressure at the airway opening (Pao) was measured through a side port at the mouthpiece using a differential pressure transducer (Sanborn, model 267 BC). Esophageal pressure (Pes) was measured with an esophageal balloon-catheter system connected to another pressure transducer (Sanborn, model DK 26730). The esophageal balloon was 10 em long and had a perimeter of 3.6 ern. The catheter had an internal diameter of 1.4 mm and a length of 100 em, During measurements, the balloon contained I ml air and was positioned as previously described (6). Transpulmonary pressure (PL) was obtained as the difference between Pao and Pes. All signals were conditioned and recorded on an ultraviolet recorder (Hewlett-Packard, modeI4560). Pulmonary flow resistance (RL) and dy1194
namic pulmonary compliance (Ctdyn) were measured during resting breathing. RLwas obtained using the isovolume method of Frank and coworkers (7); Ctdyn was determined by dividing the tidal volume by the difference in PL between points of zero flow. Minute ventilation (VE) and breathing pattern variables were obtained as average values of 10 to 15 breaths. Inspiratory (Ti), expiratory (Te), total breath duration (Ttot), and respiratory frequency (f) were obtained from flow records. Mean inspiratory flow (VT/Ti) was obtained by dividing tidal volume (VT) by Ti. Dynamic PEEPi was determined as negative deflection in esophageal pressure from the onset of inspiratory effort to the point of zero flow (figure I), as previously described (8, 9). This method assumes that the change in pleural pressure required to initiate inspiratory flow approximates the opposing level of elastic recoil pressure present at end expiration, that is, intrinsic PEEP. Such measurements of PEEPi require that at end-expiration both inspiratory and expiratory muscles be relaxed. Citterio and coworkers (10) have shown that in COPD patients the braking action of the inspiratory muscles during expiration is smaller and shorter than in normal subjects. Campbell and Friend (11) have reported that few COPD patients use the abdominal muscles during expiration while seated at rest. This is supported by recent studies of Fleury and colleagues (4) and Levine and coworkers (12). We did not measure the electrical activity of the expiratory muscles in our subjects. Our esophageal pressure records,
however, were consistent with a rapid decay in the braking action of the inspiratory muscles during expiration and the absence of expiratory muscle activity (figure I). Indeed, during expiration the esophageal pressure increased rapidly at first, and this was followed by a gradual decrease in Pes to a slightly lower value. In the presence of expiratory muscle activity, Pes should increase toward endexpiration (11). Inspiratory vital capacity (YC), forced vital capacity (FVC), forced expired volume in one second (FEV,), and maximum mid-expiratory flow rate (MMFR) were measured with a wet spirometer (Expirograph; Godart, Bilthoven, The Netherlands). Total lung capacity (TLC), functional residual capacity (FRC), and residual volume (VR)were measured with the helium dilution method, which tends to underestimate these parameters, particularly in patients with severeCOPD (13). For FEV, we used the predicted normal values of Gaensler (14). For other volumes,
(Received in original form May 9, 1989 and in revised form August 28, 1989) 1 From the Meakins-Christie Laboratories, McGill University; and the Notre Dame Hospital, Universite de Montreal, Montreal, Canada. a Supported by the MRC of Canada and the ElL JTC Memorial Research Fund. 3 Correspondence and requests for reprints should be addressed to Dr. J. Mllic-Emili, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain Street, Montreal, QC, H2X 2P2, Canada. 4 Visiting Associate Professor, McGill University.
1195
INTRINSIC PEEP IN STABLE COPO PATIENTS
the predicted values of Naimark and coworkers (15) were used. Arterial blood gases were measured with an ABL-3 analyzer (Radiometer, Copenhagen, Denmark). Regression analysis was made using the least-squares method. For data comparisons, the unpaired Student ttest was used. In addition, the model PEEPi = ax, + bx, + ... ZXn was fitted to the data by multiple linear regressionanalysis with the Number Cruncher Statistical System (NCSS), version 5.0. Statistical significance was defined as p < 0.05.
o [Fig. 1. Record of flow ('I) and esophageal pressure (Pes) illustrating method used for determining dynamic PEEPi. The latter was measured as the negative deflection of Pes from the onset of inspiratory effort to the point of zero flow (dotted line).
0.5
, inap
70 PoC02 - 45 - O.114'FEV1 (_ pmicted)
60 r - -0.50
~
:r:
Fig. 2. Relationship between PaCO, and FEV, (% predicted) in 96 patients. The dotted line indicates upper normal limits of PaCO, (= 43 mm Hg) (16).
E
p ( 0 .00 1
50
5 N
0
u
40
0
n,
30 20 0
40
20
80
60
100
FEY l (% predicted)
0' N :r:
E
Fig. 3. Relationship between PEEPi and FEV, (% predicted) in 96 patients.
~
ii: w w
n,
10 9 8 7
PEEP! - 4.14 - 0.05·F 35% predicted, namely, 5.2to 7.3em HzO (figure 3). In our patients, the relationship between arterial Pco, (mm Hg) and PEEPi (em HzO) was given by the following function (figure 5): Paeoz = 36.8 + 1.6PEEPi
(1)
The slope ofthis equation indicates that, on the average, an increase in PEEPi of 1em HzO results in an increase in Paeo z of 1.6 mm Hg. The present results can be interpreted as follows. Increasing severity of eOPD results in increased RL, which in turn causesdynamic pulmonary hyperinflation and PEEPi. Although RLis paramount
in determining dynamic hyperinflation, other factors, such as f, VT, and the braking action of the glottis and of the inspiratory muscles during expiration, should also playa role (19). In fact, multiple linear regression analysis showed that by taking into account f and VT in addition to RL, the value of r increased in our patients from 0.69 to 0.77. In the presence of a high airway resistance, an increase in f and VT makes eOPD patients especially prone to develop dynamic hyperinflation (1-3, 19). Dynamic pulmonary hyperinflation results in increased inspiratory work of breathing due to PEEPi and decreased effectiveness of the inspiratory muscles as pressure generator (4, 19). When the magnitude of the inspiratory efforts approaches the critical level, causing inspiratory muscle fatigue (22), the patients reduce their tidal volume and hence alveolar ventilation, with a concomitant increase in Paeoz. In fact, if patients with severeeOPD are asked to voluntarily restore VT to normal values, they invariably develop diaphragmatic fatigue (22), indicating that shallow breathing is an adaptive strategy used to avoid inspiratory muscle fatigue. Regional differences in PEEPi contribute to maldistribution of pulmonary ventilation and hence to impaired gas exchange, contributing to increased Paeoz and decreased Paoz' In short, dynamic pulmonary hyperinflation may play a role in causing hypercapnic respiratory failure in eOPD patients.
Acknowledgment The writers thank Mr. YvonMatte and the staff of the Lung Function Laboratory of the Notre Dame Hospital for their technical assistance. References 1. Kimball WR, Leith DE, Robins AG. Dynamic hyperinflation and ventilator dependence in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 126:991-5. 2. Gottfried SB, Rossi A, Higgs BD, et al. Noninvasive determination of respiratory system mechanics during mechanical ventilation for acute respiratory failure. Am Rev Respir Dis 1985; 131:414-20. 3. Rossi A, Gottfried SB, Zocchi L, et al. Measurement of static compliance of the total respiratory system in patients with acute respiratory failure during mechanical ventilation. Am Rev Respir Dis 1985; 131:672-7. 4. Fleury B, Murciano D, Talamo C, Aubier M, Pariente R, Milic-Emili 1. Work of breathing in
patients with chronic obstructive pulmonary disease in acute respiratory failure. Am Rev Respir Dis 1985; 131:822-27. 5. Broseghini C, Brandolese R, Poggi R, et al. Respiratory mechanics during the first day of mechanical ventilation in patients with pulmonary edema and chronic airway obstruction. Am Rev Respir Dis 1988; 138:355-61. 6. Milic-Emili1, Mead 1, Thmer 1M, Glauser EM. Improved technique for estimating pleural pressure from esophageal balloons. 1 Appl Physiol 1964; 19:207-11. 7. Frank NR, Mead 1, Ferris BG 1r. The mechanical behavior of the lungs in healthy elderly persons. 1 Clin Invest 1957; 36:1680-7. 8. Marini 11. Monitoring during mechanical ventilation. Clin Chest Med 1988; 9:73-100. 9. Petrof Bl, Legare M, Goldberg P, Milic-Emili 1, Gottfried SB. Continuous positive airway pressure reduces work of breathing and dyspnea during weaning from mechanical ventilation in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141:281-9. 10. Citterio G, Agostoni E, Del Santo A, Marazzini L. Decay ofinspiratory muscleactivity in chronic airway obstruction. 1 Appl Physiol 1981; 51:1388-97. 11. Campbell ElM, Friend 1. Action of breathing exercises in pulmonary emphysema. Lancet 1955; 1:325-9. 12. Levine S, Gillen M, Weiser P, Feiss G, Goldman M, Henson D. Inspiratory pressure generation: comparison of subjects with COPD and agematched normals. 1 Appl Physiol1988; 65:888-99. 13. Hathirat S, Renzetti AD lr, Mitchell M. Measurement of the total lung capacity by helium dilution in a constant volume system. Am Rev Respir Dis 1979; 102:760-70. 14. Gaensler EA. Evaluation of pulmonary function methods. Am Rev Med 1961; 12:385-408. 15. Naimark A, Cherniack RM, Protti D. Comprehensive respiratory information system for clinical investigation of respiratory disease. Am Rev Respir Dis 1971; 103:229-39. 16. Hertle FH, Georg R, Lange HI. Die arteriellen Blutgaspartialdriike und ihre Beziehungen zu Alter und anthropometrischen Grossen. Respiration 1971; 28:1-30. 17. Lane OJ, Howell IBL, Giblin B. Relation between airways obstruction and CO 2 tension in chronic obstructive airways disease. Br Med 1 1968; 3:707-9. 18. Shee CD, Ploy-song-song Y, Milic-Emili 1. Decay of inspiratory muscle pressure during expiration in conscious humans. 1 Appl Physiol 1985; 58:1859-65. 19. Gottfried SB, Rossi A, Milic-Emili 1. Dynamic hyperinflation, intrinsic PEEP, and the mechanically ventilated patient. Intensive Crit Care Digest 1986; 5:30-3. 20. Pepe PE, Marini 11. Occult positive endexpiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982; 126:166-70. 21. Sorli 1, Grassino A, Lorange G, Milic-Emili 1. Control of breathing in patients with chronic obstructive lung disease. Clin Sci Mol Med 1978; 54:295-304. 22. Bellemare F, Grassino A. Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. 1 Appl Physiol 1983; 55:8-15.
JANUSZ HAWSZKA,4 DANIEL A. CHARTRAND, ALEJANDRO E. GRASSINO, and JOSEPH MILlC-EMILI
Introduction
Dynamic pulmonary hyperinflation and intrinsic PEEP (PEEPi) are common in critically ill patients with chronic obstructive pulmonary disease(COPD) and have profound consequences on the energetics of breathing (1-5). In the present study, we assessed the prevalence and magnitude of PEEPi in 96 stable COPD patients with varying degrees of airway obstruction. In addition, we assessed whether PEEPi plays a role in the genesis of chronic hypercapnic ventilatory failure in COPD patients.
SUMMARY Dynamic pulmonary hyperinflation and intrinsic PEEP (PEEPi) are known to play an important role in causing acute respiratory failure in COPO patients. In the present stUdy, we have explored (1) the prevalence and magnitude of PEEPi in stable COPD patients, and (2) the correlation of PEEPi with respiratory mechanics and Paco,. In 96 stable COPD patients with varying degrees of airway obstruction, we measured pulmonary flow resistance (Rq, dynamic lung compliance (CLdyn), breathing pattern, arterial blood gases, and dynamic PEEPi. Dynamic PEEPi was determined as a negative deflection in esophageal pressure from the start of inspiratory effort to the onset of inspiratory flow. A significant correlation was found between dynamic PEEPi and FEV; -0.56, P < 0.001), between PEEPi and RL (r 0.69, P < 0.001), and between Paco2 (%predicted; r and PEEPi (r 0.6, P < 0.001). These results Indicate that increased severity of airway obstruction promotes PEEPi and concomitant dynamic hyperinflation. This implies increased inspiratory work in the face of decreased effectiveness of the inspiratory muscles as pressure generators. The present results suggest that dynamic hyperinflation may play a role in causing chronic hypoventllatlon in COPD patients. AM REV RESPIR DIS 1990; 141:1194-1197
=
=
=
Methods In this retrospective study, we used the routine lung function data and records of 96 COPD patients (18women) from the archives of the Notre Dame Hospital, Montreal. Diagnosis of their disease was based on medical history and clinical examination. Their average (±SD) age, height, and weight were 60 ± 10.8 yr, 166 ± 7.8 em, and 67 ± 15.6 kg. All measurements were made in the seated position. Airflow (V) was measured with a Fleisch No. 2 pneumotachograph (Fleisch, Lausanne, Switzerland) connected to a differential pressure transducer (Sanborn, model 270, Waltham, MA). Changes in lung volume were obtained by electronic integration of the flow signal (Hewlett-Packard, 8815A, Waltham, MA). The deadspace of the circuit was 70 ml and the equipment resistance 1.1 cm H 20/L/s. Pressure at the airway opening (Pao) was measured through a side port at the mouthpiece using a differential pressure transducer (Sanborn, model 267 BC). Esophageal pressure (Pes) was measured with an esophageal balloon-catheter system connected to another pressure transducer (Sanborn, model DK 26730). The esophageal balloon was 10 em long and had a perimeter of 3.6 ern. The catheter had an internal diameter of 1.4 mm and a length of 100 em, During measurements, the balloon contained I ml air and was positioned as previously described (6). Transpulmonary pressure (PL) was obtained as the difference between Pao and Pes. All signals were conditioned and recorded on an ultraviolet recorder (Hewlett-Packard, modeI4560). Pulmonary flow resistance (RL) and dy1194
namic pulmonary compliance (Ctdyn) were measured during resting breathing. RLwas obtained using the isovolume method of Frank and coworkers (7); Ctdyn was determined by dividing the tidal volume by the difference in PL between points of zero flow. Minute ventilation (VE) and breathing pattern variables were obtained as average values of 10 to 15 breaths. Inspiratory (Ti), expiratory (Te), total breath duration (Ttot), and respiratory frequency (f) were obtained from flow records. Mean inspiratory flow (VT/Ti) was obtained by dividing tidal volume (VT) by Ti. Dynamic PEEPi was determined as negative deflection in esophageal pressure from the onset of inspiratory effort to the point of zero flow (figure I), as previously described (8, 9). This method assumes that the change in pleural pressure required to initiate inspiratory flow approximates the opposing level of elastic recoil pressure present at end expiration, that is, intrinsic PEEP. Such measurements of PEEPi require that at end-expiration both inspiratory and expiratory muscles be relaxed. Citterio and coworkers (10) have shown that in COPD patients the braking action of the inspiratory muscles during expiration is smaller and shorter than in normal subjects. Campbell and Friend (11) have reported that few COPD patients use the abdominal muscles during expiration while seated at rest. This is supported by recent studies of Fleury and colleagues (4) and Levine and coworkers (12). We did not measure the electrical activity of the expiratory muscles in our subjects. Our esophageal pressure records,
however, were consistent with a rapid decay in the braking action of the inspiratory muscles during expiration and the absence of expiratory muscle activity (figure I). Indeed, during expiration the esophageal pressure increased rapidly at first, and this was followed by a gradual decrease in Pes to a slightly lower value. In the presence of expiratory muscle activity, Pes should increase toward endexpiration (11). Inspiratory vital capacity (YC), forced vital capacity (FVC), forced expired volume in one second (FEV,), and maximum mid-expiratory flow rate (MMFR) were measured with a wet spirometer (Expirograph; Godart, Bilthoven, The Netherlands). Total lung capacity (TLC), functional residual capacity (FRC), and residual volume (VR)were measured with the helium dilution method, which tends to underestimate these parameters, particularly in patients with severeCOPD (13). For FEV, we used the predicted normal values of Gaensler (14). For other volumes,
(Received in original form May 9, 1989 and in revised form August 28, 1989) 1 From the Meakins-Christie Laboratories, McGill University; and the Notre Dame Hospital, Universite de Montreal, Montreal, Canada. a Supported by the MRC of Canada and the ElL JTC Memorial Research Fund. 3 Correspondence and requests for reprints should be addressed to Dr. J. Mllic-Emili, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain Street, Montreal, QC, H2X 2P2, Canada. 4 Visiting Associate Professor, McGill University.
1195
INTRINSIC PEEP IN STABLE COPO PATIENTS
the predicted values of Naimark and coworkers (15) were used. Arterial blood gases were measured with an ABL-3 analyzer (Radiometer, Copenhagen, Denmark). Regression analysis was made using the least-squares method. For data comparisons, the unpaired Student ttest was used. In addition, the model PEEPi = ax, + bx, + ... ZXn was fitted to the data by multiple linear regressionanalysis with the Number Cruncher Statistical System (NCSS), version 5.0. Statistical significance was defined as p < 0.05.
o [Fig. 1. Record of flow ('I) and esophageal pressure (Pes) illustrating method used for determining dynamic PEEPi. The latter was measured as the negative deflection of Pes from the onset of inspiratory effort to the point of zero flow (dotted line).
0.5
, inap
70 PoC02 - 45 - O.114'FEV1 (_ pmicted)
60 r - -0.50
~
:r:
Fig. 2. Relationship between PaCO, and FEV, (% predicted) in 96 patients. The dotted line indicates upper normal limits of PaCO, (= 43 mm Hg) (16).
E
p ( 0 .00 1
50
5 N
0
u
40
0
n,
30 20 0
40
20
80
60
100
FEY l (% predicted)
0' N :r:
E
Fig. 3. Relationship between PEEPi and FEV, (% predicted) in 96 patients.
~
ii: w w
n,
10 9 8 7
PEEP! - 4.14 - 0.05·F 35% predicted, namely, 5.2to 7.3em HzO (figure 3). In our patients, the relationship between arterial Pco, (mm Hg) and PEEPi (em HzO) was given by the following function (figure 5): Paeoz = 36.8 + 1.6PEEPi
(1)
The slope ofthis equation indicates that, on the average, an increase in PEEPi of 1em HzO results in an increase in Paeo z of 1.6 mm Hg. The present results can be interpreted as follows. Increasing severity of eOPD results in increased RL, which in turn causesdynamic pulmonary hyperinflation and PEEPi. Although RLis paramount
in determining dynamic hyperinflation, other factors, such as f, VT, and the braking action of the glottis and of the inspiratory muscles during expiration, should also playa role (19). In fact, multiple linear regression analysis showed that by taking into account f and VT in addition to RL, the value of r increased in our patients from 0.69 to 0.77. In the presence of a high airway resistance, an increase in f and VT makes eOPD patients especially prone to develop dynamic hyperinflation (1-3, 19). Dynamic pulmonary hyperinflation results in increased inspiratory work of breathing due to PEEPi and decreased effectiveness of the inspiratory muscles as pressure generator (4, 19). When the magnitude of the inspiratory efforts approaches the critical level, causing inspiratory muscle fatigue (22), the patients reduce their tidal volume and hence alveolar ventilation, with a concomitant increase in Paeoz. In fact, if patients with severeeOPD are asked to voluntarily restore VT to normal values, they invariably develop diaphragmatic fatigue (22), indicating that shallow breathing is an adaptive strategy used to avoid inspiratory muscle fatigue. Regional differences in PEEPi contribute to maldistribution of pulmonary ventilation and hence to impaired gas exchange, contributing to increased Paeoz and decreased Paoz' In short, dynamic pulmonary hyperinflation may play a role in causing hypercapnic respiratory failure in eOPD patients.
Acknowledgment The writers thank Mr. YvonMatte and the staff of the Lung Function Laboratory of the Notre Dame Hospital for their technical assistance. References 1. Kimball WR, Leith DE, Robins AG. Dynamic hyperinflation and ventilator dependence in chronic obstructive pulmonary disease. Am Rev Respir Dis 1982; 126:991-5. 2. Gottfried SB, Rossi A, Higgs BD, et al. Noninvasive determination of respiratory system mechanics during mechanical ventilation for acute respiratory failure. Am Rev Respir Dis 1985; 131:414-20. 3. Rossi A, Gottfried SB, Zocchi L, et al. Measurement of static compliance of the total respiratory system in patients with acute respiratory failure during mechanical ventilation. Am Rev Respir Dis 1985; 131:672-7. 4. Fleury B, Murciano D, Talamo C, Aubier M, Pariente R, Milic-Emili 1. Work of breathing in
patients with chronic obstructive pulmonary disease in acute respiratory failure. Am Rev Respir Dis 1985; 131:822-27. 5. Broseghini C, Brandolese R, Poggi R, et al. Respiratory mechanics during the first day of mechanical ventilation in patients with pulmonary edema and chronic airway obstruction. Am Rev Respir Dis 1988; 138:355-61. 6. Milic-Emili1, Mead 1, Thmer 1M, Glauser EM. Improved technique for estimating pleural pressure from esophageal balloons. 1 Appl Physiol 1964; 19:207-11. 7. Frank NR, Mead 1, Ferris BG 1r. The mechanical behavior of the lungs in healthy elderly persons. 1 Clin Invest 1957; 36:1680-7. 8. Marini 11. Monitoring during mechanical ventilation. Clin Chest Med 1988; 9:73-100. 9. Petrof Bl, Legare M, Goldberg P, Milic-Emili 1, Gottfried SB. Continuous positive airway pressure reduces work of breathing and dyspnea during weaning from mechanical ventilation in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1990; 141:281-9. 10. Citterio G, Agostoni E, Del Santo A, Marazzini L. Decay ofinspiratory muscleactivity in chronic airway obstruction. 1 Appl Physiol 1981; 51:1388-97. 11. Campbell ElM, Friend 1. Action of breathing exercises in pulmonary emphysema. Lancet 1955; 1:325-9. 12. Levine S, Gillen M, Weiser P, Feiss G, Goldman M, Henson D. Inspiratory pressure generation: comparison of subjects with COPD and agematched normals. 1 Appl Physiol1988; 65:888-99. 13. Hathirat S, Renzetti AD lr, Mitchell M. Measurement of the total lung capacity by helium dilution in a constant volume system. Am Rev Respir Dis 1979; 102:760-70. 14. Gaensler EA. Evaluation of pulmonary function methods. Am Rev Med 1961; 12:385-408. 15. Naimark A, Cherniack RM, Protti D. Comprehensive respiratory information system for clinical investigation of respiratory disease. Am Rev Respir Dis 1971; 103:229-39. 16. Hertle FH, Georg R, Lange HI. Die arteriellen Blutgaspartialdriike und ihre Beziehungen zu Alter und anthropometrischen Grossen. Respiration 1971; 28:1-30. 17. Lane OJ, Howell IBL, Giblin B. Relation between airways obstruction and CO 2 tension in chronic obstructive airways disease. Br Med 1 1968; 3:707-9. 18. Shee CD, Ploy-song-song Y, Milic-Emili 1. Decay of inspiratory muscle pressure during expiration in conscious humans. 1 Appl Physiol 1985; 58:1859-65. 19. Gottfried SB, Rossi A, Milic-Emili 1. Dynamic hyperinflation, intrinsic PEEP, and the mechanically ventilated patient. Intensive Crit Care Digest 1986; 5:30-3. 20. Pepe PE, Marini 11. Occult positive endexpiratory pressure in mechanically ventilated patients with airflow obstruction. Am Rev Respir Dis 1982; 126:166-70. 21. Sorli 1, Grassino A, Lorange G, Milic-Emili 1. Control of breathing in patients with chronic obstructive lung disease. Clin Sci Mol Med 1978; 54:295-304. 22. Bellemare F, Grassino A. Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. 1 Appl Physiol 1983; 55:8-15.
