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The effect of transpulmonary pressure on airway smooth-muscle contraction
The effect of transpulmonary pressure on airway smooth-muscle contraction Walter G. Wolfe, M.D. (by invitation), Durham, N. C, J. A. Nadel, M.D. (by invitation), and Paul Graf (by invitation), San Francisco, Calif. Sponsored by David C. Sabiston, Jr., M.D., Durham, N. C.
Ihe tracheobronchial tree has been regarded as a passive conducting system resembling the larger arteries, having both rather ineffective smooth-muscle contractile tissue and a passive response to transmural mechanical forces. However, pathologic conditions such as asthma or changes in bronchomuscular tone due to inhalation of pharmacologic aerosols make it obvious that bronchoconstriction can profoundly modify the normal function of the respiratory system and affect the distribution of ventilation and gas exchange. Previous studies in man have demonstrated that resistance to airflow decreases as lung volume increases. Therefore, the present study was designed to determine the relative contribution of airway smoothmuscle tone versus other components of the airway wall in determining airflow re-
From the Department of Surgery, Duke University Medical Center, Durham, N. C. 27710, and The Cardiovascular Research Institute, University of California School of Medicine, San Francisco, Calif. 94122. Supported in part by a Program Project Grant HL-06285 from The National Heart and Lung Institute. Read at the Fifty-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., May 1, 2, and 3, 1972.
sistance and airway dimensions with changing lung volume. Methods Twenty dogs were anesthetized with chloralose (50 mg. per kilogram intravenously) and urethane (500 mg. per kilogram intravenously), tracheostomies were performed, the respiratory muscles were paralyzed with succinylcholine, and the lungs were ventilated artificially with a Harvard respirator. Transpulmonary pressure was measured by inserting a No. 10 Malecot catheter through one of the intercostal spaces into the intrapleural space and connecting it to one side of a Sanborn differential strain gauge (No. 267 BC), the other side of which was connected to an opening on the side of the tracheal cannula. Airflow was measured with a Fleisch pneumotachograph and a Statham differential strain gauge. A volume signal was obtained by electrical integration of the flow signal. Forced sinusoidal oscillations of airflow (2 cycles per second) were produced by a loudspeaker system enclosed in an airtight box and driven by a low-frequency sine wave generator and power amplifier. During the measurements, the respirator was 757
The Journal of
7 58
Wolfe, Nadel, Graf
Thoracic and Cardiovascular Surgery
AIRTIGHTBOX
DIFFERENTIAL f STRAIN GAUGE (Prp)
PLEURAL SPACE
"0
Fig. 1. Diagram of apparatus used to vary transpulmonary pressure ( F T P ) , stimulate the cervical vagus nerves, and measure total pulmonary resistance.
5
10 15 20 25 30 Transpulmonary Pressurelcm H20)
Fig. 2. Effect of transpulmonary pressure on total pulmonary resistance (/?L) with the vagi cut (X X) and with the vagi stimulated at 5 volts ( O O ) , 7 volts ( • • ) and 13 volts ( A -A).
stopped, the oscillating loudspeaker system was connected to the tracheal cannula, and total pulmonary resistance was measured by means of a method of electrical subtraction.1 Transpulmonary pressure was changed by increasing or decreasing pressure in the box in order to perform resistance measurements at different lung volumes (Fig. 1). Airway smooth-muscle tone was altered by stimulation of the peripheral ends of the cut vagus nerves electrically at a constant frequency (15 per second) and duration (3 msec.) with variation of the intensity of stimulus (5 to 15 volts) to change the degree of airway tone. Bronchograms were obtained by delivering tantalum powder into the lungs.2 Chest roentgenograms (95 kvp., 60 Ma., % 0 to % 0 second) were taken at a distance of 40 cm. During each study, the respirator was stopped, and transpulmonary pressure was adjusted to the desired level. Transpulmonary pressure and pulmonary resistance were measured in the control state, and a roentgenogram was obtained. The vagus nerves were then stimulated for 10 seconds, and the measurements were repeated.
state with the vagi cut, increasing transpulmonary pressure from 5 to 20 cm. H 2 0 had no significant effect on pulmonary resistance. During electrical stimulation of the vagi, pulmonary resistance increased markedly at low transpulmonary pressures. For example, at a transpulmonary pressure of 4 cm. H , 0 , pulmonary resistance increased thirtyfold during vagal stimulation at a high intensity (13 volts). With increasing transpulmonary pressure, vagal stimulation had a diminished effect on pulmonary resistance. When transpulmonary pressure was greater than 20 cm. H 2 0 , vagal stimulation was no longer capable of increasing pulmonary resistance (Fig. 2 ) . Effect of transpulmonary pressure on airway diameter. Stimulation of the vagus nerves at low transpulmonary pressures constricted the airways from the trachea to the smallest bronchi visible on the roentgenogram (Fig. 3 ) . With increasing transpulmonary pressure, vagal stimulation had a diminished effect on airway dimensions (Figs. 4 and 5 ) .
Results
Discussion
Effect of transpulmonary pressure on total pulmonary resistance. In the control
During inspiration, as the intrapleural pressure becomes more negative and the
Volume 64 Number 5
Airway smooth-muscle contraction
November, 1972
759
Fig. 3. Bronchogram of a dog at a transpulmonary pressure of 10 cm. H 2 0. A, Control. B, Film taken during vagal stimulation (intensity 13 v.). The airways from the trachea to the smallest bronchi visible are constricted.
Fig. 4. Bronchogram of the same dog at a transpulmonary pressure of 30 cm. FLO. A, Control. B, Film taken during vagal stimulation (intensity 13 volts). There is no measurable change in airway diameter.
lungs expand, the greater elastic tension in the lungs distends the bronchi, while the more negative intrapleural pressure distends the intrathoracic but extrapulmonary trachea and bronchi. Total airway volume therefore increases. The increase in volume of the airways and its relationship to the degree of inflation of the lungs depends on the compliance of both the airways and the lungs.3 It is likely that, during inflation of the lungs, the intrapulmonary airways and lungs in-
crease in volume proportionally. This conclusion is consistent with pressure-volume measurements of the trachea and bronchi, including those in man.4 These studies ignore the possible influence of changes in smooth-muscle tone or assume that they would be insignificant. It would seem desirable to relate the caliber of the airways assessed by measurement to the total lung volume and measure airway resistance, but this is justifiable only if compliance of the lungs
7 60
The Journal of
Wolfe, Nadel, Graf
Thoracic and Cardiovascular Surgery
30 r 25 20
Trachea
Mainstem Bronchus
ntermediate Bronchus
Small Bronchus 0 10 20 30 Transpulmonary Pressure (cm H20) Fig. 5. Effect of transpulmonary pressure on the diameters of different airways in a dog during control ( • • ) and during stimulation of the vagi (intensity 13 volts) ( O O ) - Vagal stimulation of the airway smooth muscle has no significant effect on airway diameter at a transpulmonary pressure above 20 cm. H 2 0.
is constant. The caliber of airways is determined more directly by transpulmonary pressure, and therefore by the elastic pull of the lungs, than by lung volume. 5 ' 6 Although spontaneous inflation of the lungs corresponds to dilation of the airways, this can be an entirely passive effect. However, it has been suggested that airway smooth muscle may relax on inspiration. Since physiologic conditions alter the tone of airway smooth muscle, the functional results of these changes must be sought. Airway caliber balances two conflicting factors, airway volume related to dead space ventilation and resistance to airflow. Severe airway constriction may be undesirable due to an increase in resistance even if dead space decreases; however, a large increase in airway volume may be disadvantageous if the need for increased ventilation of dead
space outweighs the benefits of decreased resistance to flow.7 Present studies indicate that the distensibility of the airways in dogs is markedly affected by the state of the smooth-muscle tone. When the vagi were cut and cholinergic tone abolished, increasing transpulmonary pressure above resting lung volume had no significant effect on resistance to airflow. However, when tone developed during vagal stimulation, resistance was influenced markedly by transpulmonary pressure. At low distending forces, bronchoconstriction was diminished progressively with increasing transpulmonary pressure. In fact, it was not possible to increase resistance to airflow at transpulmonary pressures above 20 cm. H , 0 regardless of the intensity of vagal stimulation. These results were confirmed when the airways were studied roentgenographically. Increasing the tone of airway smooth muscle had a striking effect on the resting dimensions of airways at low transpulmonary pressures but did not affect them significantly at high transpulmonary pressures. Thus the state of tone in airways has a varying effect on airway mechanics, depending on the state of distention of the lungs. Summary In this study the state of tone in airway smooth muscle in dogs had a variable effect on the dimensions of the airways and on airflow resistance, depending on the degree of distention of the lungs. At resting lung volume, increasing airway tone resulted in marked airway narrowing and increased airflow resistance. The measurement of total pulmonary resistance and of airway diameter demonstrated that increasing lung volume lessened the ability of the airways to narrow. REFERENCES 1 Mead, J., and Whittenberger, J. L.: Physical Properties of Human Lungs Measured During Spontaneous Respiration, J. Appl. Physiol. 5: 779, 1953. 2 Nadel, J. A., Wolfe, W. G., and Graf, P. D.: Powdered Tantalum as a Medium for Bron-
Volume 64 Number 5 November, 1972
chography in Canine and Human Lungs, Invest. Radiol. 3: 229, 1968. 3 Widdicombe, J. G., and Nadel, J. A.: Airway Volume, Airway Resistance, and Work and Force of Breathing: Theory, J. Appl. Physiol. 18: 863, 1963. 4 Croteau, J. R., and Cook, C. D.: VolumePressure and Length-Tension Measurements in Human Tracheal and Bronchial Segments, J. Appl. Physiol. 16: 170, 1961. 5 Severinghaus, J. W., and Stupfel, M.: Respiratory Dead Space Increase Following Atropine
Airway smooth-muscle contraction 7 6 1
in Man, and Atropine, Vagal, or Ganglionic Blockade and Hypothermia in Dogs, J. Appl. Physiol. 8: 81, 1955. 6 Caro, C. G., Butler, J., and Dubois, A. B.: Some Effects of Restriction of Chest Cage Expansion on Pulmonary Function in Man: An Experimental Study, J. Clin. Invest. 39: 573, 1960. 7 Widdicombe, J. G.: The Activity of Pulmonary Stretch Receptors During Bronchoconstriction, Pulmonary Oedema, Atelectasis and Breathing Against a Resistance, J. Physiol. 159: 436, 1961.
Ihe tracheobronchial tree has been regarded as a passive conducting system resembling the larger arteries, having both rather ineffective smooth-muscle contractile tissue and a passive response to transmural mechanical forces. However, pathologic conditions such as asthma or changes in bronchomuscular tone due to inhalation of pharmacologic aerosols make it obvious that bronchoconstriction can profoundly modify the normal function of the respiratory system and affect the distribution of ventilation and gas exchange. Previous studies in man have demonstrated that resistance to airflow decreases as lung volume increases. Therefore, the present study was designed to determine the relative contribution of airway smoothmuscle tone versus other components of the airway wall in determining airflow re-
From the Department of Surgery, Duke University Medical Center, Durham, N. C. 27710, and The Cardiovascular Research Institute, University of California School of Medicine, San Francisco, Calif. 94122. Supported in part by a Program Project Grant HL-06285 from The National Heart and Lung Institute. Read at the Fifty-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., May 1, 2, and 3, 1972.
sistance and airway dimensions with changing lung volume. Methods Twenty dogs were anesthetized with chloralose (50 mg. per kilogram intravenously) and urethane (500 mg. per kilogram intravenously), tracheostomies were performed, the respiratory muscles were paralyzed with succinylcholine, and the lungs were ventilated artificially with a Harvard respirator. Transpulmonary pressure was measured by inserting a No. 10 Malecot catheter through one of the intercostal spaces into the intrapleural space and connecting it to one side of a Sanborn differential strain gauge (No. 267 BC), the other side of which was connected to an opening on the side of the tracheal cannula. Airflow was measured with a Fleisch pneumotachograph and a Statham differential strain gauge. A volume signal was obtained by electrical integration of the flow signal. Forced sinusoidal oscillations of airflow (2 cycles per second) were produced by a loudspeaker system enclosed in an airtight box and driven by a low-frequency sine wave generator and power amplifier. During the measurements, the respirator was 757
The Journal of
7 58
Wolfe, Nadel, Graf
Thoracic and Cardiovascular Surgery
AIRTIGHTBOX
DIFFERENTIAL f STRAIN GAUGE (Prp)
PLEURAL SPACE
"0
Fig. 1. Diagram of apparatus used to vary transpulmonary pressure ( F T P ) , stimulate the cervical vagus nerves, and measure total pulmonary resistance.
5
10 15 20 25 30 Transpulmonary Pressurelcm H20)
Fig. 2. Effect of transpulmonary pressure on total pulmonary resistance (/?L) with the vagi cut (X X) and with the vagi stimulated at 5 volts ( O O ) , 7 volts ( • • ) and 13 volts ( A -A).
stopped, the oscillating loudspeaker system was connected to the tracheal cannula, and total pulmonary resistance was measured by means of a method of electrical subtraction.1 Transpulmonary pressure was changed by increasing or decreasing pressure in the box in order to perform resistance measurements at different lung volumes (Fig. 1). Airway smooth-muscle tone was altered by stimulation of the peripheral ends of the cut vagus nerves electrically at a constant frequency (15 per second) and duration (3 msec.) with variation of the intensity of stimulus (5 to 15 volts) to change the degree of airway tone. Bronchograms were obtained by delivering tantalum powder into the lungs.2 Chest roentgenograms (95 kvp., 60 Ma., % 0 to % 0 second) were taken at a distance of 40 cm. During each study, the respirator was stopped, and transpulmonary pressure was adjusted to the desired level. Transpulmonary pressure and pulmonary resistance were measured in the control state, and a roentgenogram was obtained. The vagus nerves were then stimulated for 10 seconds, and the measurements were repeated.
state with the vagi cut, increasing transpulmonary pressure from 5 to 20 cm. H 2 0 had no significant effect on pulmonary resistance. During electrical stimulation of the vagi, pulmonary resistance increased markedly at low transpulmonary pressures. For example, at a transpulmonary pressure of 4 cm. H , 0 , pulmonary resistance increased thirtyfold during vagal stimulation at a high intensity (13 volts). With increasing transpulmonary pressure, vagal stimulation had a diminished effect on pulmonary resistance. When transpulmonary pressure was greater than 20 cm. H 2 0 , vagal stimulation was no longer capable of increasing pulmonary resistance (Fig. 2 ) . Effect of transpulmonary pressure on airway diameter. Stimulation of the vagus nerves at low transpulmonary pressures constricted the airways from the trachea to the smallest bronchi visible on the roentgenogram (Fig. 3 ) . With increasing transpulmonary pressure, vagal stimulation had a diminished effect on airway dimensions (Figs. 4 and 5 ) .
Results
Discussion
Effect of transpulmonary pressure on total pulmonary resistance. In the control
During inspiration, as the intrapleural pressure becomes more negative and the
Volume 64 Number 5
Airway smooth-muscle contraction
November, 1972
759
Fig. 3. Bronchogram of a dog at a transpulmonary pressure of 10 cm. H 2 0. A, Control. B, Film taken during vagal stimulation (intensity 13 v.). The airways from the trachea to the smallest bronchi visible are constricted.
Fig. 4. Bronchogram of the same dog at a transpulmonary pressure of 30 cm. FLO. A, Control. B, Film taken during vagal stimulation (intensity 13 volts). There is no measurable change in airway diameter.
lungs expand, the greater elastic tension in the lungs distends the bronchi, while the more negative intrapleural pressure distends the intrathoracic but extrapulmonary trachea and bronchi. Total airway volume therefore increases. The increase in volume of the airways and its relationship to the degree of inflation of the lungs depends on the compliance of both the airways and the lungs.3 It is likely that, during inflation of the lungs, the intrapulmonary airways and lungs in-
crease in volume proportionally. This conclusion is consistent with pressure-volume measurements of the trachea and bronchi, including those in man.4 These studies ignore the possible influence of changes in smooth-muscle tone or assume that they would be insignificant. It would seem desirable to relate the caliber of the airways assessed by measurement to the total lung volume and measure airway resistance, but this is justifiable only if compliance of the lungs
7 60
The Journal of
Wolfe, Nadel, Graf
Thoracic and Cardiovascular Surgery
30 r 25 20
Trachea
Mainstem Bronchus
ntermediate Bronchus
Small Bronchus 0 10 20 30 Transpulmonary Pressure (cm H20) Fig. 5. Effect of transpulmonary pressure on the diameters of different airways in a dog during control ( • • ) and during stimulation of the vagi (intensity 13 volts) ( O O ) - Vagal stimulation of the airway smooth muscle has no significant effect on airway diameter at a transpulmonary pressure above 20 cm. H 2 0.
is constant. The caliber of airways is determined more directly by transpulmonary pressure, and therefore by the elastic pull of the lungs, than by lung volume. 5 ' 6 Although spontaneous inflation of the lungs corresponds to dilation of the airways, this can be an entirely passive effect. However, it has been suggested that airway smooth muscle may relax on inspiration. Since physiologic conditions alter the tone of airway smooth muscle, the functional results of these changes must be sought. Airway caliber balances two conflicting factors, airway volume related to dead space ventilation and resistance to airflow. Severe airway constriction may be undesirable due to an increase in resistance even if dead space decreases; however, a large increase in airway volume may be disadvantageous if the need for increased ventilation of dead
space outweighs the benefits of decreased resistance to flow.7 Present studies indicate that the distensibility of the airways in dogs is markedly affected by the state of the smooth-muscle tone. When the vagi were cut and cholinergic tone abolished, increasing transpulmonary pressure above resting lung volume had no significant effect on resistance to airflow. However, when tone developed during vagal stimulation, resistance was influenced markedly by transpulmonary pressure. At low distending forces, bronchoconstriction was diminished progressively with increasing transpulmonary pressure. In fact, it was not possible to increase resistance to airflow at transpulmonary pressures above 20 cm. H , 0 regardless of the intensity of vagal stimulation. These results were confirmed when the airways were studied roentgenographically. Increasing the tone of airway smooth muscle had a striking effect on the resting dimensions of airways at low transpulmonary pressures but did not affect them significantly at high transpulmonary pressures. Thus the state of tone in airways has a varying effect on airway mechanics, depending on the state of distention of the lungs. Summary In this study the state of tone in airway smooth muscle in dogs had a variable effect on the dimensions of the airways and on airflow resistance, depending on the degree of distention of the lungs. At resting lung volume, increasing airway tone resulted in marked airway narrowing and increased airflow resistance. The measurement of total pulmonary resistance and of airway diameter demonstrated that increasing lung volume lessened the ability of the airways to narrow. REFERENCES 1 Mead, J., and Whittenberger, J. L.: Physical Properties of Human Lungs Measured During Spontaneous Respiration, J. Appl. Physiol. 5: 779, 1953. 2 Nadel, J. A., Wolfe, W. G., and Graf, P. D.: Powdered Tantalum as a Medium for Bron-
Volume 64 Number 5 November, 1972
chography in Canine and Human Lungs, Invest. Radiol. 3: 229, 1968. 3 Widdicombe, J. G., and Nadel, J. A.: Airway Volume, Airway Resistance, and Work and Force of Breathing: Theory, J. Appl. Physiol. 18: 863, 1963. 4 Croteau, J. R., and Cook, C. D.: VolumePressure and Length-Tension Measurements in Human Tracheal and Bronchial Segments, J. Appl. Physiol. 16: 170, 1961. 5 Severinghaus, J. W., and Stupfel, M.: Respiratory Dead Space Increase Following Atropine
Airway smooth-muscle contraction 7 6 1
in Man, and Atropine, Vagal, or Ganglionic Blockade and Hypothermia in Dogs, J. Appl. Physiol. 8: 81, 1955. 6 Caro, C. G., Butler, J., and Dubois, A. B.: Some Effects of Restriction of Chest Cage Expansion on Pulmonary Function in Man: An Experimental Study, J. Clin. Invest. 39: 573, 1960. 7 Widdicombe, J. G.: The Activity of Pulmonary Stretch Receptors During Bronchoconstriction, Pulmonary Oedema, Atelectasis and Breathing Against a Resistance, J. Physiol. 159: 436, 1961.