CARBON DIOXIDE AND THE WORK OF BREATHING John C. Parker, … , Richard M. Peters, Thomas B. Barnett J Clin Invest. 1963;42(8):1362-1372. https://doi.org/10.1172/JCI104820. Research Article Find the latest version: https://jci.me/104820/pdf Journal of Clinical Investigation Vol. 42, No. 8, 1963 CARBON DIOXIDE AND THE WORK OF BREATHING* BY JOHN C. PARKER, RICHARD M. PETERS, AND THOMAS B. BARNETT (From the Departments of Medicine and Surgery, The University of North Carolina School of Medicine, North Carolina Memorial Hospital, Chapel Hill, N. C.) (Submitted for publication April 30, 1962; accepted May 2, 1963) It is well-known that within certain concentra- These last two studies suggest that the alteration tion limits carbon dioxide increases the work of in pulmonary mechanics associated with CO2 breathing simply by acting on the respiratory cen- breathing is due to bronchoconstriction with in- ter to stimulate hyperventilation. There is evi- creased airway resistance. In contrast, in isolated dence that CO2 also affects work of breathing by perfused lungs, Nisell (8) and others have shown virtue of its tendency to cause bronchoconstriction that increased CO2 in the ventilating gas causes with increased airway resistance. bronchodilatation. Einthoven (1) demonstrated in dogs ventilated Attinger (9) measured the pulmonary compli- with a pump that end-inspiratory pressure in- ance, transpulmonary resistance, and functional creased when the gas mixture ventilating the lungs residual capacity in dogs with an esophageal bal- contained high concentrations of CO2. Dixon and loon to measure intrathoracic pressure and a Brodie (2) found that when animals were simi- plethysmograph to determine the flow and volume larly ventilated with gases containing high con- changes. With administration of 5 and 10%o C02, centrations of CO2, the expiratory phase was pro- minute volume increased and functional residual longed and the lungs trapped air. They noted capacity decreased, but the changes in compliance that vagotomy prevented these changes. Daly, and resistance were not considered significant. Lamberton, and Schweitzer (3) studied the re- Butler, Caro, Alcala, and DuBois (10), using sistance to inflation of the lungs in cross-circula- DuBois's closed-plethysmograph method in hu- tion experiments in which the blood returning mans, found that ventilation with 4 to 10% CO2 from one dog's lungs was used to perfuse another caused no change in airway resistance. dog's brain. They demonstrated that an animal We undertook this investigation to determine whose brain received blood with a high pCO2 more specifically the nature of the effects of hyper- developed increased resistance to lung inflation as capnia on respiratory mechanics and the work of determined by the method of Konsett and Rossler breathing. (4). Peters (5), using the same method, showed that the increase in resistance to lung inflation was METHODS proportional to arterial pCO2 when dogs were In order to determine the effect of CO2 on the me- ventilated with gases with high CO2. Atropine chanical properties of the lung alone, the other effects of and vagotomy prevented these changes. CO2 had to be controlled. Any method allowing the ani- These studies showed that CO2 affected lung mals to breathe spontaneously during CO, administration would inevitably lead to an alteration in the rate and mechanics, but gave no information about whether depth of respiration. If the position or depth of respira- the change was in the elastic or viscous (flow- tion were altered, the end-inspiratory or end-expiratory resistive) properties of the lung. Roy and Brown volume might be outside the range of linear pressure- in 1885 (6) found that the pressure in an endo- volume relationship. This would cause an apparent bronchial balloon increased with asphyxia, pre- change in compliance without any actual change in the to elastic properties of the lung. Changes in lung volume sumably owing bronchoconstriction; vagotomy and in the rate of air flow would also introduce uncon- prevented this increase. Kilburn (7) demon- trollable variations in airway resistance due to changes strated with bronchograms that inhalation of 5%o in bronchial caliber and in the ratio of turbulent to laminar CO2 decreased the bronchial diameter by 15%o. flow. The use of controlled respiration in animals given muscle-paralyzing agents was unsatisfactory, since these * This work was supported by U. S. Public Health agents cause an increase in bronchial secretions unless Service grant H-1257. atropine or atropine-like drugs are given. Therefore, 1362 CARBON DIOXIDE AND THE WORK OF BREATHING 1363 the best method available was measurement of pulmo- control bleeding and the Stryker saw to divide the ster- nary mechanics in experimental animals with lungs ex- num. The tracheal cannula was connected to the pump p)osed at thoracotomy and ventilation at all times care- described above just before the chest was opened. The fully controlled by respirator pump. A pump was con- two edges of the sternum were widely retracted with the structed to withdraw at all times exactly the volume of rib spreader, and both phrenic nerves clamped and di- gas delivered without causing the animal to rebreathe its vided. In those experiments in which the vagus nerve own expired gas.' The pump was equipped with two was to be stimulated, the carotid sheath in the neck was solenoid valves so timed that during one pump cycle, the opened, and the nerve was isolated so that it could be animal was ventilated and during the next, the pump was divided and its distal end stimulated electrically. The evacuated and refilled. Thus, there was a pause equal to femoral artery was exposed and cannulated with a poly- one respiratory cycle at the end of each expiration and no ethylene catheter, which was attached to a 3-way stopcock inspiratory pause. The tidal volume of this pump could so that blood samples could be withdrawn and blood be varied from 0 to 1,000 ml, and the frequency, from 0 pressure monitored with a Statham P23D manometer. to 22 respiratory cycles per minute. The inspiratory and Transpulmonary pressure was measured with a Statham expiratory flow rates could be controlled independently. ±2 pounds per inch2 differential manometer. One cham- Signals for volume and flow rate were generated re- ber of this instrument was connected to the tracheal can- spectively by a potentiometer and generator attached to nula, and the other was left open to the atmosphere. the piston of the pump. The accuracy of the volume and The volume, transpulmonary pressure, flow rate, and blood flow measurements made with this respirator was checked pressure were all suitably amplified and simultaneously by recording the flow rate simultaneously with a parallel recorded on an Offner multichannel recorder. The ma- plate flow resistor (linear range, 0 to 100 L per minute). nometer used to measure airway pressure was calibrated Across this was connected a Statham +0.05 pounds per against water after each experimental period. Cervical inch2 differential manometer. The signal from this flow- vagotomy was done in two of the dogs, and the vagus was meter was electronically integrated to give volume. Con- stimulated with a Harvard apparatus stimulator using ditions occurring in most of these experiments were then 15 v at 100 cycles per second. simulated, and recordings made and analyzed. The dis- In five studies, once the chest had been opened and the crepancy in time between the volume and flow measure- lungs exposed, the dogs were placed in an airtight, 50- ments recorded by the pump and those by the flow inte- gallon plethysmograph. When thermal equilibrium was grator system was never greater than 0.03 seconds. reached, the plethysmograph was sealed, and gains or Plots of data made from both recording systems coincided losses in the dog's lung volume were recorded as pressure almost exactly when superimposed. Although this pump changes in the plethysmograph with a Statham +0.15 was designed to withdraw at all times exactly the volume pounds per inch2 manometer, In experiments with the delivered, it still did not assure maintenance of the same plethysmograph, transpulmonary pressure was measured lung volume. In a system of this type, any deviation of as the difference between the pressure in the airway and RQ from unity might be expected to cause a progres- that within the plethysmograph. sive change in the lung volume over the course of the In these experiments, after the operative procedure, the experiment. When a gas mixture high in CO2 is admin- position, rate, and volume of respiration were adjusted istered to a previously normocapnic animal, one might so that the lungs seemed to be in a normal mid-position expect an acute decrease in RQ, as CO2 accumulates in and not over- or underinflated. After all adjustments, the animal's tissues, until equilibrium is attained. The volume, flow rate, transpulmonary pressure, plethysmo- opposite effect would be expected on return to room air. graphic pressure, and blood pressure were recorded with Since the pressure in the pump during inspiration and the dog breathing air. Three to four complete respira- expiration would not be exactly the same, it was also tory cycles were included. The time of this first reading possible for this to cause the lungs to change volume. was that from which all times noted in Tables I and II This would occur because the pump would fill itself at were calculated. The test gas-25% 02, 10 to 20%o atmospheric pressure and force this air into the animal's CO., and nitrogen to make 100%-was then admin- lungs at an increased pressure; then it would withdraw istered for 3 to 10 minutes, and recordings were repeated air at less than atmospheric pressure and refill at atmos- once or more during this period, usually at 3-minute pheric pressure.