ESSAYS ON APS CLASSIC PAPERS Dead space: Simplicity to complexity

CONSIDERABLE UNCERTAINTY existed regarding the magnitude of pulmonary dead space in the immediate post-World War II era. The dead space concept was originated by Bohr (2), who viewed total ventilation as composed of two distinct, but homogeneous, components—alveolar ventilation that participated fully in gas exchange and dead space ventilation in which no respiratory exchange occurred. With knowledge of the composition of inspired air, Bohr used a mass balance approach to calculate dead space from measurements of tidal volume and mixed and expired alveolar gas compositions. The validity of the latter variable was at the root of discrepancies in dead space values reported in the literature before Fowler’s work (4). Multiple methods for sampling alveolar gas (6) had been used, and the choice of alveolar sample led to discrepant estimates of dead space. Douglas and Haldane (3) used the Haldane-Priestley method to measure alveolar carbon dioxide fraction and reported a fourfold increase in resting dead space when tidal volume increased with exercise. These findings were criticized by Krogh and Lindhard (8), who employed hydrogen as a tracer and a better means of alveolar sampling. The latter authors concluded that dead space varied relatively little—less than 100 ml despite widely differing respiratory maneuvers. Although subsequent reports supported their conclusion, the issues still were not clearly defined when Fowler began his studies. Values of dead space were important because at that time alveolar ventilation was calculated from total ventilation and an assumed or empiric value for dead space. An interesting series of events intersected to improve conceptual and quantitative understanding of dead space. In 1946, Julius Comroe accepted the Chairmanship of the Department of Physiology and Pharmacology of the Graduate School of Medicine at the University of Pennsylvania (7). Comroe developed a coordinated program to investigate pulmonary function in health and disease. He recruited a number of noweminent scientists, one of whom was Ward S. Fowler. At the same time, John C. Lilly (10) in the Johnson Foundation at the University of Pennsylvania, together with J. P. Hevesy, was developing a rapidly responding nitrogen meter (response rate of 0.02 s) for the Air Force to test for leakage in respiratory masks. Lilly and colleagues (9) earlier had invented a sensitive capacitance manometer. Lilly (11) constructed a flowmeter consisting of a laminar resistor that produced small changes in pressure proportional to flow. The combination of the manometer and laminar resistor allowed continuous measurements of airflow throughout the respiratory cycle. Hence, Fowler was in an excellent position to investigate the respiratory dead space with the instrumentation from the Johnson Foundation and the “advice and encouragement” of Julius Comroe (4). Unlike previous investigators, Fowler did not need to rely on analysis of a single aliquot of expired air to estimate alveolar composition, but he could choose an appropriate value from the continuous recordings of nitrogen concentration and expired airflow. The latter signal was laboriously integrated over time to provide a record of cumulative expired volume. Fowler (4) used a tidal breath of pure oxygen that completely filled the dead space and mixed with alveolar gas downstream of the dead space. He described three phases in the subsequent expired nitrogen-volume recording. The initial portion of the expired gas (I) contained no nitrogen, and the last phase (III) contained a “relatively constant” nitrogen concentration representing the dilution of the pre-existing alveolar nitrogen by the inspired oxygen. The short intermediate second phase (II) of the experimental plot was characterized by a transient increase in nitrogen concentration from the initial dead space to final alveolar values. Fowler recognized that a square wave change in nitrogen concentration would not be